MODULATION OF CHEMOSENSORY RECEPTORS AND LIGANDS ASSOCIATED THEREWITH

• US 20080306093A1
• Filed: 06/08/2007
• Published: 12/11/2008
• Est. Priority Date: 06/08/2007
• Status: Active Grant

• Current Assignee: Firmenich Inc (DSM-Firmenich AG)
• Original Assignee: Senomyx Inc (DSM-Firmenich AG)
• Inventors: Zhang, Feng, Chen, Qing, Li, Xiaodong, Zoller, Mark, Servant, Guy, Fine, Richard, Tachdjian, Catherine, Zlotnik, Albert, Werner, Sara, Kang, Xinshan, Tang, Xiao-Qing, Rinnova, Marketa, Liu, Haitian, Klebansky, Boris
• Granted Patent: US 9,603,848 B2
• Time in Patent Office: Days
• US Class Current: 514/260.1
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: C07D 239/80 Oxygen atoms
• CPC Class Codes: C07D 239/95 with hetero atoms directly attached in positions 2 and 4
• CPC Class Codes: C07D 239/96 Two oxygen atoms
• CPC Class Codes: C07D 285/15 Six-membered rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: G01N 2333/726 G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
• CPC Class Codes: G01N 2500/04 Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 33/74 involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
• CPC Class Codes: G16B 15/00 ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
• CPC Class Codes: G16B 15/20 Protein or domain folding
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/30 Detection of binding sites or motifs
• CPC Class Codes: G16B 20/50 Mutagenesis

Abstract

The present invention provides screening methods for identifying modifiers of chemosensory receptors and their ligands, e.g., by determining whether a test entity is suitable to interact with one or more interacting sites within the Venus flytrap domains of the chemosensory receptors as well as modifiers capable of modulating chemosensory receptors and their ligands.

Claims

1. A method of screening for a candidate of a chemosensory receptor ligand modifier comprising

determining whether a test entity is suitable to interact with a chemosensory receptor via a first interacting site within the Venus flytrap domain of the chemosensory receptor.

2. The method of claim 1, wherein the first interacting site of the Venus flytrap domain of the chemo sensory receptor includes one or more interacting residues of the Venus flytrap domain of the chemosensory receptor.

3. The method of claim 1, wherein the first interacting site of the Venus flytrap domain of the chemosensory receptor includes one or more interacting spaces of the Venus flytrap domain of the chemosensory receptor.

4. The method of claim 1, wherein the first interacting site of the Venus flytrap domain includes an interacting space identified based on one or more interacting residues.

5. The method of claim 1, wherein the first interacting site of the Venus flytrap domain of the chemo sensory receptor includes one or more interacting residues, which are identified based on mutagenesis analysis of the Venus flytrap domain.

6. The method of claim 1, wherein the first interacting site of the Venus flytrap domain is identified based on computer modeling, X-ray crystallography, or a combination thereof.

7. The method of claim 1, wherein the first interacting site of the Venus flytrap domain is identified based on one or more known chemosensory receptor ligands.

8. The method of claim 1, wherein the first interacting site of the Venus flytrap domain is identified based on one or more known chemosensory receptor ligand modifiers.

9. The method of claim 1, wherein the first interacting site of the Venus flytrap domain is identified based on a predetermined chemosensory receptor ligand.

10. The method of claim 1, wherein the first interacting site of the Venus flytrap domain is predetermined.

11. The method of claim 1, wherein the first interacting site of the Venus flytrap domain is in the T1R2 Venus flytrap domain.

12. The method of claim 1, wherein the first interacting site of the Venus flytrap domain is in the T1R2 Venus flytrap domain and is identified in the presence of T1R3 Venus flytrap domain.

13. The method of claim 1, wherein the determination is carried out in silico.

17. The method of claim 1, wherein the first interacting site includes an interacting residue selected from the group consisting of amino acid N 143, S144, and 1167 of a human T1R2 and a combination thereof.

18. The method of claim 1, wherein the first interacting site includes an interacting residue selected from the group consisting of amino acid S40, S 144, S165, Y103, D142, and P277 of a human T1R2 and a combination thereof.

19. The method of claim 1, wherein the first interacting site includes an interacting residue selected from the group consisting of amino acid K65, R383, D307, E302, and D278 of a human T1R2 and a combination thereof.

20. The method of claim 1, wherein the first interacting site includes an interacting residue selected from the group consisting of amino acid 1167, P185, T184, T326, E302, V384, A305, I325, I306, R383, D307, E382, D278, I279, I67, V66, V309, D142, S165, S40, S303, T242, F103, Q328, and S168 of a human T1R2 and a combination thereof.

21. The method of claim 1, wherein the first interacting site includes an interacting residue selected from the group consisting of amino acid N143, S144, I167, S40, S144, S165, Y103, D142, P277, K65, R383, D307, E302, D278, P185, T184, T326, E302, V384, A305, I325, I306, D307, E382, I279, I67, V66, V309, S303, T242, F103, Q328, and S168 of a human T1R2 and a combination thereof.

22. The method of claim 1, wherein the first interacting site includes a group of interacting residues selected from the group consisting of 1) N 143, S144, and I167 of a human T1R2, 2) S40, S144, S165, Y103, D142, P277 or a human T1R2, 3) K65, R383, D307, E302, and D278 of a human T1R2, 4) I167, P185, T184, T326, E302, V384, A305, I325, I306, R383, D307, E382, D278, I279, I67, V66, V309, D142, S165, S40, S303, T242, F103, Q328, and S168 of a human T1R2, 5) N143, S144, I167, S40, S144, S165, Y103, D142, P277, 1(K65, R383, D307, E302, D278, P185, T184, T326, E302, V384, A305, I325, I306, E382, I279, I67, V66, V309, S303, T242, F103, Q328, and S168 of a human T1R2, and 6) a combination thereof.

23. The method of claim 1, wherein the first interacting site includes an interacting residue selected from the group consisting of amino acid K65, D278, L279, D307, R383 and V384 of a human T1R2 and a combination thereof and wherein a test entity suitable to interact with the first interacting site of the chemosensory receptor is indicative of a candidate of a chemosensory receptor ligand enhancer.

24. The method of claim 1, wherein the first interacting site includes an interacting residue selected from the group consisting of amino acid S40, S144, Y 103, D 142, P277 of a human T1R2 and a combination thereof wherein a test entity suitable to interact with the first interacting site of the chemosensory receptor is indicative of a candidate of an enhancer for sucrose or sucralose.

25. The method of claim 1, wherein the test entity is a designed compound structure.

26. The method of claim 1, wherein the chemosensory receptor ligand is a sweet flavor entity selected from the group consisting of cyclamic acid, mogroside, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, aspartame, aspartame derivatives, neotame, saccharin, sucralose, acesulfame K, glucose, erythritol, D-tryptophan, glycine, mannitol, sorbitol, maltitol, lactitol, isomalt, hydroganeted glucose syrup (HGS), hydrogenated starch hydrolyzate (HSH), stevioside, rebaudioside A, sweet Stevia-based glycosides, alitame, carrelame, guanidine-based sweeteners, tagatose, xylitol, and high fructose corn syrup.

35. A chemosensory receptor ligand modifier identified by the method of claim 1.

37. A chemosensory receptor ligand enhancer identified by the method of claim 1 and having a structural formula selected from the group consisting of 1) structural Formula (I):

or a salt, hydrate, solvate or N-oxide thereof wherein;

G forms a single bond with either D or E and a double bond with the other of D or E;

R¹ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR³, —

S(O)_aR³, NR³R⁴, —

CONR³R⁴, —

CO₂R³, —

NR³CO₂R⁴, —

NR³CONR⁴R⁵, —

NR³CSNR⁴R⁵ or —

NR³C(=NH)NR⁴R⁵, —

SO₂NR³R³⁴, —

NR³SO₂R⁴ , —

NR³SO₂NR⁴R⁵, —

B(OR³)(OR⁴), —

P(O)(OR³) or —

P(O)(R³)(OR⁴);

R² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁶, —

S(O)_bR⁶, —

NR⁶R⁷, —

CONR⁶R⁷, —

CO₂R⁶, —

NR⁶CONR⁷R⁸, —

NR⁶CSNR⁷R⁸ or —

NR⁶C(=NH)NR⁷R⁸, —

SO₂NR⁵R⁶, —

NR⁵SO₂R⁶, —

NR⁵SO₂NR⁶R⁷, —

B(OR⁵)(OR⁶), —

P(O)(OR⁵)(OR⁶), —

P(O)(R⁵)(OR⁶) or alternatively, R¹ and R² together with the atoms to which they are bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring where the ring is optionally fused to another aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

with the proviso that R¹ and R² are not both hydrogen;

A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁹, —

S(O)_cR⁹, —

NR⁹R¹⁰, —

NOR⁹, —

CONR⁹R¹⁰, —

CO₂R⁹, —

NR⁹CO₂R¹⁰, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹ or —

NR⁹C(=NH)NR¹⁰R¹¹;

B is —

N—

or —

C(R¹²)—

;

R¹² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

NR¹³R¹⁴, —

CN, —

OR¹³, —

S(O)_dR¹³, CO₂R¹³ or —

CONR¹³R¹⁴;

G is —

C—

or —

S(O)₂—

;

provided that when G is —

S(O)₂—

, G forms a single bond with E;

D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo, chloro, fluoro, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

OR¹⁵ —

NOR¹⁵, —

S(O)_eR¹⁵, —

NR¹⁵R¹⁶, —

NCN, , —

CO₂R¹⁵, —

CONR¹⁵R¹⁶ when the bond between D and G is a single bond;

D is =O, =S, =N—

OR¹⁵, =NHNHR¹⁵ when G form a double bond with D;

n is 0 when G is —

S(O)₂—

and n is 1 when G is —

C—

;

E is —

NR¹⁷, —

N—

or —

C(R¹⁸)—

;

provided that E is —

NR¹⁷—

only when G forms a single bond with E;

R¹⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or —

CO₂R¹⁹;

R¹⁸ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

NR²⁰R²¹, —

CN, —

OR²⁰, —

S(O)_fR²⁰, —

CO₂R²⁰ or —

CONR²⁰R²¹;

a, b, c, d, e and f are independently 0, 1 or 2; and

R³—

R¹¹, R¹³—

R¹⁶, R¹⁸, R²⁰ and R²¹ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R³ and R⁴, R⁴ and R⁵, R⁶ and R⁷, R⁷ and R⁸, R⁹ and R¹⁰, R¹⁰ and R¹¹, R¹³ and R¹⁴, R¹⁵ and R¹⁶ and R²⁰ and R²¹ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring,

2) structural Formula (XVI);

or a salt, solvate, hydrate or N-oxide thereof wherein;

each G is independently —

C(R⁷⁷)(R⁷⁹)—

, —

C(O)—

, —

NR⁷⁷—

or—

S(O)₂—

;

n is 1, 2 or 3;

provided that when n is greater than one then only one G is —

C(O)—

, —

C(S), —

S(O)₂—

or —

NR⁷⁷—

;

Y is —

C(O)—

, —

C(S) or —

S(O)₂—

;

R⁷⁰ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁷⁷, S(O)_aR⁷², —

NR⁷²R⁷³, CONR⁷² R⁷³,—

CO₂R⁷², —

NR⁷²CO₂R⁷³, —

NR⁷²CONR⁷³R⁷⁴, —

NR⁷²CSNR⁷³R⁷⁴ or —

NR⁷²C(=NH)NR⁷³R⁷⁴ , —

SO₂NR⁷²R⁷³, —

NR⁷²SO₂R⁷³, —

NR⁷²SO₂NR⁷³R⁷⁴, —

B(OR⁷²)(OR⁷³), —

P(O)(OR⁷²)(OR⁷³) or —

P(O)(R⁷²)(OR⁷³);

R⁷¹ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁷⁴, —

S(O)_bR⁷⁴, —

NR⁷⁴R⁷⁵, —

CONR⁷⁴R⁷⁵, —

CO₂R⁷⁴, —

NR⁷⁴ CO₂R⁷⁴, —

NR⁷⁴CONR⁷⁵R⁷⁶, —

NR⁷⁴CSNR⁷⁵R⁷⁶ or —

NR⁷⁴C(=NH)NR⁷⁵R⁷⁶, —

SO₂NR⁷⁴R⁷⁵, —

NR⁷⁴SO₂R⁷⁵, —

NR⁷⁴SO₂NR⁷⁵R⁷⁶, —

B(OR⁷⁴)(OR⁷⁵), —

P(O)(OR⁷⁴)(OR⁷⁵), —

P(O)(R⁷⁴)(OR⁷⁵) or alternatively, R⁷¹ and R⁷² together with the atoms to which they are bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring where the ring is optionally fused to another aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

a and b are independently 0, 1 or 2;

R⁷²—

R⁷⁶ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R⁷² and R⁷³, R⁷³ and R⁷⁴, R⁷⁴ and R⁷⁵ and R⁷⁵ and R⁷⁶ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and

R⁷⁷—

R⁷⁹ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R⁷⁷ and R⁷⁸, together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring, and

3) structural Formula (XXII);

or a salt, solvate, hydrate or N-oxide thereof wherein;

each G is independently —

C(R⁹⁴)(R⁹⁵)—

, —

C(O)—

, —

NR⁹⁴—

or —

S(O)₂—

;

n is 1, 2 or 3;

provided that when n is greater than one then only one G is —

C(O)—

, —

S(O)₂—

or —

NR⁹⁴—

;

Y is —

C(O)—

, —

C(S)—

or —

S(O)₂—

;

L is —

C(R¹⁰⁴)(R¹⁰⁵)—

, —

O—

, or —

NR¹⁰⁴—

;

R⁹² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁹⁸, —

S(O)_yR⁹⁸, —

NR⁹⁸R⁹⁹, —

CONR⁹⁸ R⁹⁹, —

CO₂R⁹⁸, —

NR⁹⁸ CO₂R⁹⁹, —

NR⁹⁸CONR⁹⁹R¹⁰⁰ , —

NR⁹⁸CSNR⁹⁹R¹⁰⁰ or—

NR⁹⁸C(=NH)NR⁹⁹R¹⁰⁰, —

SO₂NR⁹⁸R⁹⁹, —

NR⁹⁸SO₂R⁹⁹, —

NR⁹⁸SO₂NR⁹⁹R¹⁰⁰, —

B(OR⁹⁸)(OR⁹⁹), —

P(O)(OR⁹⁸)(OR⁹⁹) or —

P(O)(R⁹⁸)(OR⁹⁹);

R⁹³ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR¹⁰¹, —

S(O)_zR¹⁰¹, —

NR^{101 R102}, —

CONR¹⁰¹R¹⁰² , —

CO₂R¹⁰¹, —

NR¹⁰¹CO₂R¹⁰², —

NR¹⁰¹CONR¹⁰²R¹⁰³, —

NR¹⁰¹CSNR¹⁰²R¹⁰³ or —

NR¹⁰¹C(=NH)NR¹⁰²R¹⁰³, —

SO₂NR¹⁰¹R¹⁰², —

NR¹⁰¹SO₂R¹⁰², —

NR¹⁰¹SO₂NR¹⁰²R¹⁰³, —

B(OR¹⁰¹)(OR¹⁰²), —

P(O)(OR¹⁰¹)(OR¹⁰²), —

P(O)(R¹⁰¹)(OR¹⁰²) or alternatively, R⁹² and R⁹³ together with the atoms to which they are bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring where the ring is optionally fused to another aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

y and z are independently 0, 1 or 2;

R⁹⁸—

R¹⁰³ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R⁹⁸ and R⁹⁹, R⁹⁹ and R¹⁰⁰, R¹⁰¹ and R¹⁰² and R¹⁰¹ and R¹⁰² together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

R⁹⁴—

R⁹⁵ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R⁹⁴ and R⁹⁵, together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

R⁹⁶ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and

R¹⁰⁴—

R¹⁰⁵ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R¹⁰⁴ and R¹⁰⁵, together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring.

14. A method of screening for a candidate of a chemosensory receptor ligand modifier comprising

determining whether a test entity is suitable to interact with a chemosensory receptor via a first interacting site within the Venus flytrap domain of the chemosensory receptor,

wherein the first interacting site is identified in light of a second interacting site identified based on the interaction between a chemosensory receptor ligand and the chemosensory receptor.

15. The method of claim 14, wherein the first and second interacting site are in the T1R2 Venus flytrap domain.

16. The method of claim 14, wherein the first and second interacting site are in the Ti R2 Venus flytrap domain and identified in the presence of T1R3 Venus flytrap domain.

27. A method of screening for a candidate of a chemosensory receptor modifier comprising

determining whether a test entity is suitable to interact with a chemosensory receptor via an interacting site within the Venus flytrap domain of the chemosensory receptor,

wherein the interacting site includes an interacting residue selected from the group consisting ofN143, S144, I167, S40, S144, S165, Y103, D142, P277, K65, R383, D307, E302, D278, P185, T184, T326, E302, V384, A305, I325, I306, D307, E382, I279, I67, V66, V309, S303, T242, F103, Q328, and S168 of a human T1R2 and a combination thereof,

wherein a test entity suitable to interact with the interacting site of the chemosensory receptor is indicative of a candidate of a chemosensory receptor modifier.

28. The method of claim 27, wherein the interacting site includes an interacting residue selected from the group consisting of amino acid N143, S144, and I167 of a human T1R2 and a combination thereof.

29. The method of claim 27, wherein the interacting site includes an interacting residue selected from the group consisting of amino acid S40, S 144, Y103, D142, and P277 of a human T1R2 and a combination thereof.

30. The method of claim 27, wherein the interacting site includes an interacting residue selected from the group consisting of I167, P185, T184, T326, E302, V384, A305, I325, I306, R383, D307, E382, D278, I279, I67, V66, V309, D142, S 165, S40, S303, T242, F103, Q328, and S168 of a human T1R2 and a combination thereof.

31. The method of claim 27, wherein the interacting site is in the T1R2 Venus flytrap domain.

32. The method of claim 27, wherein the interacting site is in the T1R2 Venus flytrap domain and identified in the presence of T1R3 Venus flytrap domain.

33. The method of claim 27, wherein the determination is carried out in silico.

34. The method of claim 27, wherein the test entity is a designed compound structure.

36. A chemosensory receptor modifier identified by the method of claim 27.

38. A method of modulating the activity of a chemosensory receptor ligand comprising contacting a chemosensory receptor ligand modifier with a cell containing T1R2 Venus flytrap domain in the presence of a chemosensory receptor ligand, wherein the chemo sensory receptor ligand modifier interacts with an interacting site of the chemosensory receptor.

39. The method of claim 38, wherein the interacting site of the chemosensory receptor includes an interacting residue selected from the group consisting of amino acid N143, S144, and I167 of a human T1R2 and a combination thereof.

40. The method of claim 38, wherein the interacting site of the chemosensory receptor includes an interacting residue selected from the group consisting of amino acid S40, S144, S165, Y103, D142, and P277 of a human T1R2 and a combination thereof.

41. The method of claim 38, wherein the interacting site of the chemosensory receptor includes an interacting residue selected from the group consisting of amino acid K65, R383, D307, E302, and D278 of a human T1R2 and a combination thereof.

42. The method of claim 38, wherein the interacting site of the chemosensory receptor includes an interacting residue selected from the group consisting of amino acid I167, P185, T184, T326, E302, V384, A305, I325, I306, R383, D307, E382, D278, I279, I67, V66, V309, D142, S165, S40, S303, T242, F103, Q328, and S168 of a human T1R2 and a combination thereof.

43. The method of claim 38, wherein the interacting site includes an interacting residue selected from the group consisting of amino acid N143, S144, I167, S40, S144, S165, Y103, D142, P277, K65, R383, D307, E302, D278, P185, T184, T326, E302, V384, A305, I325, I306, D307, E382, I279, I67, V66, V309, S303, T242, F103, Q328, and S168 of a human T1R2 and a combination thereof.

44. The method of claim 38, wherein the interacting site includes a group of interacting residues of K65, D278, L279, D307, R383, and V384 of a human T1R2 and wherein the chemosensory receptor ligand modifier enhances the activity of a chemosensory receptor ligand.

45. The method of claim 38, wherein the interacting site includes a group of interacting residues of S40, S144, Y103, D142, and P277 of a human T1R2 and wherein the chemosensory receptor ligand is selected from the group consisting of sucrose and sucralose.

46. The method of claim 38, wherein the chemosensory receptor ligand modifier stabilizes a close conformation within T1R2 Venus flytrap domain formed by the interaction between the chemosensory receptor ligand and the chemosensory receptor.

47. The method of claim 38, wherein the chemosensory receptor ligand modifier is a chemosensory receptor ligand enhancer and has a structural formula selected from the group consisting ofstructural Formula (I):

or a salt, hydrate, solvate or N-oxide thereof wherein;

G forms a single bond with either D or E and a double bond with the other of D or E;

R¹ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR³, —

S(O)_aR³, —

NR³R⁴, —

CONR³R⁴, —

CONR³R⁴, —

CO₂R³, —

NR³CONR^4R5, —

NR³CSNR⁴R⁵ or —

NR³C(=NH)NR⁴R⁵, —

SO₂NR³R⁴, —

NR³SO₂R⁴, —

NR³SO₂NR⁴R⁵, —

B(OR³)(OR⁴), —

P(O)(OR³)(OR⁴) or —

P(O)(R³)(OR⁴);

R² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁶, —

S(O)_bR⁶, —

NR⁶R⁷, —

CONR⁶R⁷, —

CO₂R⁶, —

NR⁶CO₂R⁷, —

NR⁶CONR⁷R⁸, —

NR⁶CSNR⁷ R⁸ or —

NR⁶C(=NH)NR⁷R⁸, —

SO₂NR⁵R⁶, —

NR⁵SO²R⁶, —

NR⁵SO₂NR⁶R⁷, —

B(OR⁵)(OR⁶), —

P(O)(OR⁵)(OR⁶), —

P(O)(R⁵)(OR⁶) or alternatively, R¹ and R² together with the atoms to which they are bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring where the ring is optionally fused to another aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

with the proviso that R¹ and R² are not both hydrogen;

A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁹, —

S(O)_cR⁹, —

NR⁹R¹⁰, —

NOR⁹, —

CONR⁹R¹⁰, —

CO₂R⁹, —

NR⁹CO₂R¹⁰, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹ or —

NR⁹C(=NH)NR¹⁰R¹¹;

B is —

N—

or —

C(R¹²—

;

R¹² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

NR¹³R¹⁴, —

CN, —

OR¹³, —

S(O)_dR¹³, —

CO₂R¹³ or —

CONR¹³R¹⁴;

G is —

C—

or —

S(O)₂—

;

provided that when G is —

S(O)₂—

, G forms a single bond with E;

D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo, chloro, fluoro, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

OR¹³, —

NOR¹⁵, —

S(O)_eR¹⁵, —

NR¹⁵R¹⁶, —

NCN, , —

CO₂R¹⁵, —

CONR¹⁵R¹⁶ when the bond between D and G is a single bond;

D is =O, =S, =N—

OR¹⁵, =NHNHR¹⁵ when G form a double bond with D;

n is 0 when G is —

S(O)₂—

and n is 1 when G is —

C—

;

E is —

NR¹⁷—

, —

N—

or—

C(R¹⁸)—

;

provided that E is —

NR¹⁷—

only when G forms a single bond with E;

R¹⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or —

CO₂R¹⁹;

R¹⁸ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

NR²⁰R²¹, —

CN, —

OR²⁰, —

S(O)_fR²⁰, —

CO₂R²⁰ or —

CONR²⁰ R²¹;

a, b, c, d, e and f are independently 0, 1 or 2; and

R<sup>3—

R11</sup>, R¹³—

R¹⁶, R¹⁸, R²⁰ and R²¹ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R³ and R^4, R⁴ and R⁵, R⁶ and R⁷, R⁷ and R⁸, R⁹ and R¹⁰, R¹⁰ and R¹¹, R¹³ and R¹⁴, R¹⁵ and R¹⁶ and R²⁰ and R²¹ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring,

2) structural Formula (XVI);

or a salt, solvate, hydrate or N-oxide thereof wherein;

each G is independently —

C(R⁷⁷)(R⁷⁹)—

, —

C(O)—

, —

NR⁷⁷—

or—

S(O)₂—

;

n is 1, 2 or 3;

provided that when n is greater than one then only one G is —

C(O)—

, —

C(S), —

S(O)₂—

or —

NR⁷⁷—

;

Y is —

C(O)—

, —

C(S) or —

S(O)₂—

;

R⁷⁰ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁷², —

S(O)_aR⁷², —

NR⁷²R⁷³, —

CONR⁷²R⁷³, —

CO₂R⁷², —

NR⁷²CO₂R⁷³, —

NR⁷²CONR⁷³R⁷⁴, —

NR⁷²CSNR⁷³R⁷⁴ or —

NR⁷²C(=NH)NR⁷³R⁷⁴, —

SO₂NR⁷²R⁷³, —

NR⁷²SO₂R⁷³, —

NR⁷²SO₂NR⁷³R⁷⁴, —

B(OR⁷²)(OR⁷³), —

P(O)(OR⁷²)(OR⁷³) or —

P(O)(R⁷²)(OR⁷³);

R⁷¹ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁷⁴, —

S(O)_bR⁷⁴, —

NR⁷⁴R⁷⁴, —

CONR⁷⁴R⁷⁵, —

CO₂R⁷⁴, —

NR⁷⁴CO₂R⁷⁵, —

NR⁷⁴ CONR⁷⁵R⁷⁶, —

NR⁷⁴CSNR⁷⁵R⁷⁶ or —

NR⁷⁴C(=NH)NR⁷⁵R⁷⁶, —

SO₂NR⁷⁴R⁷⁵, —

NR⁷⁴SO₂R⁷⁵, —

NR⁷⁴SO₂NR⁷⁵R⁷⁶, —

B(OR⁷⁴)(OR⁷⁵), —

P(O)(OR⁷⁴)(OR⁷⁵), —

P(O)(R⁷⁴)(OR⁷⁵) or alternatively, R⁷¹ and R⁷² together with the atoms to which they are bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring where the ring is optionally fused to another aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

a and b are independently 0, 1 or 2;

R⁷²—

R⁷⁶ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R⁷² and R⁷³ , R⁷³ and R⁷⁴, R⁷⁴ and R⁷⁵ and R⁷⁵ and R⁷⁶ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and

R⁷⁷—

R⁷⁹ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R⁷⁷ and R⁷⁸, together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring, and

3) structural Formula (XXII);

or a salt, solvate, hydrate or N-oxide thereof wherein;

each G is independently —

C(R⁹⁴)(R⁹⁵)—

, —

C(O)—

, —

NR⁹⁴—

or—

S(O)₂—

;

n is 1, 2 or 3;

provided that when n is greater than one then only one G is —

C(O)—

, —

S(O)₂—

or—

NR⁹⁴—

;

Y is —

C(O)—

, —

C(S)—

or —

S(O)₂—

;

L is —

C(R¹⁰⁴)(R¹⁰⁵)—

, —

O—

, or—

NR¹⁰⁴—

;

R⁹² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁹⁸, —

S(O)_yR⁹⁸, —

NR⁹⁸R⁹⁹, —

CONR⁹⁸R⁹⁹, —

CO₂R⁹⁸, —

NR⁹⁸CO₂R⁹⁹, —

NR⁹⁸CONR⁹⁹R¹⁰⁰, —

NR⁹⁸CSNR⁹⁹R¹⁰⁰ or —

NR⁹⁸C(=NH)NR⁹⁹R¹⁰⁰, —

SO₂NR⁹⁸R⁹⁹, —

NR⁹⁸SO₂R⁹⁹, —

NR⁹⁸SO₂NR⁹⁹R¹⁰⁰, —

B(OR⁹⁸)(OR⁹⁹), —

P(O)(OR⁹⁸)(OR⁹⁹) or —

P(O)(R⁹⁸)(OR⁹⁹);

R⁹³ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR¹⁰¹, —

S(O)_zR¹⁰¹, —

NR¹⁰¹R¹⁰², —

CONR¹⁰¹R¹⁰², —

CO₂R¹⁰¹, —

NR¹⁰¹CO₂R¹⁰², —

NR¹⁰¹CONR¹⁰²R¹⁰³, —

NR¹⁰¹CSNR¹⁰²R¹⁰³ or —

NR¹⁰¹C(=NH)NR¹⁰²R¹⁰³, —

SO₂NR¹⁰¹R¹⁰², —

NR¹⁰¹SO₂R¹⁰², —

NR¹⁰¹SO₂NR¹⁰²R¹⁰³, —

B(OR¹⁰¹)(OR¹⁰²), —

P(O)(OR¹⁰¹)(OR¹⁰²), —

P(O)(R¹⁰¹)(OR¹⁰²) or alternatively, R⁹² and Rtogether with the atoms to which they are bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring where the ring is optionally fused to another aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

y and z are independently 0, 1 or 2;

R⁹⁸—

R¹⁰³ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R⁹⁸ and R⁹⁹, R⁹⁹ and R¹⁰⁰, R¹⁰¹ and R¹⁰² and R¹⁰¹ and R¹⁰² and R¹⁰¹ and R¹⁰² together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

R⁹⁴—

R⁹⁵ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R⁹⁴ and R⁹⁵, together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

R⁹⁶ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and

R¹⁰⁴—

R¹⁰⁵ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R¹⁰⁴ and R¹⁰⁵, together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring.

48. The method of claim 38, wherein the cell contains T1R2 Venus flytrap domain within a GPCR pathway.

49. The method of claim 38, wherein the chemosensory receptor ligand modifier is provided in a comestible composition.

50. The method of claim 38, wherein the chemosensory receptor ligand modifier is provided in a medicinal composition.

51. The method of claim 38, wherein the chemo sensory receptor ligand modifier is provided in a food or beverage product.

52. A chemosensory receptor ligand modifier, wherein in the presence of a chemo sensory receptor ligand it interacts with T1R2 Venus flytrap domain via at least three interacting residues selected from the group consisting of N143, S144, I167, S40, S144, S165, Y103, D142, P277, K65, R383, D307, E302, D278, P185, T184, T326, E302, V384, A305, I325, I306, E382, I279, I67, V66, V309, S303, T242, F103, Q328, and S168 of a human T1R2.

53. The chemosensory receptor ligand modifier of claim 52, wherein it interacts with T1R2 Venus flytrap domain via a group of amino acids selected from the group consisting of 1) N143, S144, and I167 of a human T1R2, 2) S40, S144, S165, Y103, D142, P277 or a human T1R2, 3) K65, R383, D307, E302, and D278 of a human T1R2, 4) I167, P185, T184, T326, E302, V384, A305, I325, I306, R383, D307, E382, D278, 279, I67, V66, V309, D142, S165, S40, S303, T242, F103, Q328, and S168 ofa human T1R2, and 5) N143, S144, I167, S40, S144, S165, Y103, D142, P277, K65, R383, D307, E302, D278, P185, T184, T326, E302, V384, A305, I325, I306, E382, I279, I67, V66, V309, S303, T242, F 103, Q328, and S168 of a human T1R2.

54. The chemosensory receptor ligand modifier of claim 52, wherein it interacts with T1R2 Venus flytrap domain via a group of amino acids K65, D278, L279, D307, R383, and V384 of a human T1R2 and wherein it enhances the activity of a chemosensory receptor ligand.

55. The chemosensory receptor ligand modifier of claim 52, wherein it interacts with TR2 Venus flytrap domain via a group of amino acids of S40, S144, Y103, D142, P277 of a human T1R2 in the presence of sucrose or sucralose and wherein it enhances the activity of sucrose or sucralose.

56. The chemosensory receptor ligand modifier of claim 52, wherein it is a chemosensory receptor ligand enhancer and has the structural Formula (I):

or a salt, hydrate, solvate or N-oxide thereof wherein;

G forms a single bond with either D or B and a double bond with the other of D or B;

R¹ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR³, —

S(O)_aR³, —

NR³R⁴, CONR³R⁴, —

CO₂R³, —

NR³CO₂R⁴, —

NR³CONR⁴R⁵, —

NR³CSNR⁴R⁵ or —

NR³C(=NH)NR⁴R⁵, —

SO₂NR³R⁴, —

NR³SO₂R⁴, —

NR³SO₂NR⁴R⁵, —

B(OR³)(OR⁴), —

P(O)(OR³)(OR⁴) or —

P(O)(R³)(OR⁴);

R² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁶, —

S(O)_bR⁶, —

NR⁶R7, —

CONR⁶ R⁷, —

CO₂R⁶, —

NR⁶ CO₂R⁷, —

NR⁶CONR⁷R⁸, —

NR⁶CSNR⁷R⁸ or —

NR⁶C(=NH)NR⁷R⁸, —

SO₂NR⁵R⁶, —

NR⁵SO₂R⁶, —

NR⁵SO₂NR⁶R⁷, —

B(OR⁵)(OR⁶), —

P(O)(OR⁵)(OR⁶), —

P(O)(R⁵)(OR⁶) or alternatively, R¹ and R² together with the atoms to which they are bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring where the ring is optionally fused to another aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

with the proviso that R¹ and R² are not both hydrogen;

A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁹, —

S(O)_cR⁹, —

NR⁹R¹⁰, —

NOR⁹, —

CONR⁹R¹⁰, —

CO₂R⁹, —

NR⁹CO₂R¹⁰, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹ or —

NR⁹C(=NH)NR¹⁰R¹¹;

B is —

N—

or —

C(R¹²)—

;

R¹² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

NR¹³R¹⁴, —

CN, —

OR¹³, —

S(O)_dR¹³, —

CO₂R¹³ or —

CONR¹³R¹⁴;

G is —

C—

or—

S(O)₂—

;

provided that when G is —

S(O)₂—

, G forms a single bond with E;

D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo, chloro, fluoro, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

OR¹⁵, —

NOR¹⁵, —

S(O)_eR¹⁵, —

NR¹⁵R¹⁶, —

NCN, , —

CO₂R¹⁵, —

CONR¹⁵R¹⁶ when the bond between D and G is a single bond;

D is =O, =S, =N—

OR¹⁵, =NHNHR¹⁵ when G form a double bond with D;

n is 0 when G is —

S(O)₂—

and n is 1 when G is —

C—

;

E is —

NR¹⁷—

, —

N—

or—

C(R¹⁸)—

;

provided that E is —

NR¹⁷—

only when G forms a single bond with E;

R¹⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or —

CO₂R¹⁹;

R¹⁸ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

NR²⁰R²¹, —

CN, —

OR²⁰, —

S(O)_fR²⁰, —

CO₂R²⁰ or —

CONR²⁰R²¹;

a, b, c, d, e and f are independently 0, 1 or 2; and

R³—

R¹¹, R¹³—

R¹⁶, R¹⁸, R²⁰ and R²¹ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R³ and R^4, R⁴ and R^5, R⁶ and R^7, R⁷ and R⁸, R⁹ and R¹⁰, R¹⁰ and R¹¹, R¹³ and R¹⁴, R¹⁵ and R¹⁶ and R²⁰ and R²¹ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

57. The ligand modifier of claim 56 in which R¹ is hydrogen, alkyl, substituted alkyl, —

CN, —

NO₂, —

OR², —

S(O)_aR³, —

NR³R⁴, —

CONR³R⁴, —

CO₂R³ and R² is hydrogen, alkyl, substituted alkyl, —

CN, —

NO₂, —

OR⁶, —

S(O)_bR⁶, —

NR⁶R⁷, —

CONR⁶R⁷ or —

CO₂R⁶.

58. The ligand modifier of claim 56 in which R¹ is hydrogen, —

CH₃, —

OH, —

NH₂, —

OR³ or13-CO₂R³ and R² is —

CH₃, —

OH, —

NH₂, —

OR⁵ or —

CO₂R⁶ and R³ and R⁶ are independently hydrogen or —

CH₃.

59. The ligand modifier of claim 56 in which R¹ and R² together with the atoms to which they are bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring.

60. The ligand modifier of claim 56 of structural Formula (II):

wherein;

Y forms a single bond with either W or Z and a double bond with the other of W or Z;

W is —

C(R²⁴)—

, —

S—

, —

N—

, —

N(R²⁵)—

or —

O—

;

Y is —

C(R²⁶)—

or —

N—

;

Z is —

C(R ²⁷)—

, —

S—

, —

N—

, —

N(R²⁸)—

, or —

O—

;

R²⁴ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl —

CN, —

NO₂, —

OR²⁹, —

S(O)_gR²⁹, —

NR²⁹R³⁰, —

CONR²⁹R³⁰, —

CO₂R²⁹, —

SO₂NR²⁹R<sub>, —

NR</sub>²⁹SO₂R³⁰, —

B(OR²⁹)(OR³⁰), —

P(O)(OR²⁹)(OR³⁰) or —

P(O)(R²⁹)(OR³⁰);

R²⁶ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl —

CN, —

NO₂, —

OR³¹, —

S(O)_hR³¹, —

NR³¹R³², —

CONR³¹R³², —

CO₂R³¹, —

SO₂NR³¹R³², —

NR³¹SO₂R³², —

B(OR³¹)(OR³²), —

P(O)(OR³¹)(OR³²) or —

P(O)R³¹)(OR³²);

R²⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl —

CN, —

NO₂, —

OR³³, —

S(O)_iR³³, —

NR³³R³⁴, —

CONR³³R³⁴, —

CO₂R³³, —

SO₂NR³³R³⁴, —

NR³³SO₂R³⁴, —

B(OR³³)(OR³⁴), —

P(O)(OR³³)(OR³⁴) or —

P(O)(R³³)(OR³⁴) or alternatively R²⁴ and R²⁶ or R²⁶ and R²⁷ together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

g, h and i are independently 0 or 1;

R²⁵ and R²⁸ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and

R²⁹ —

R³⁴ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl alternatively R²⁹ and R³⁰, R³¹ and R³² and R³³ and R³⁴ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

with the provisos that when either W and Z is —

O—

or —

S—

the other of W and Z is not —

O—

or —

S—

and Y is —

C(R²⁶)—

and W is —

NR²⁵—

only when Z is —

N—

and Z is —

NR²⁸—

only when W is —

N—

.

61. The ligand modifier of claim 56 of structural Formula (III):

wherein;

H is —

C(R³⁵ )—

or —

N—

;

I is —

C(R³⁶) or —

N—

;

J is —

C(R³⁷)—

or —

N—

;

K is —

C(R³⁸)—

or —

N—

;

R³⁵ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo, chioro, fluoro, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, —

CN, —

NO₂, —

OR³⁹, —

S(O)_jR³⁹, —

NR³⁹R⁴⁰, —

CONR³⁹R⁴⁰, —

CO₂R³⁹, —

SO₂NR³⁹R⁴⁰, —

NR³⁹SO₂R⁴⁰, —

B(OR³⁹)(OR⁴⁰), —

P(O)(OR³⁹)(OR⁴⁰) or —

P(O)(R³⁹)(OR⁴⁰);

R³⁶ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo, chioro, fluoro, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁴¹, —

S(O)_kR⁴¹, —

NR⁴¹R⁴², —

CONR⁴¹R⁴², —

CO₂R⁴¹, —

SO₂NR⁴¹R⁴², —

NR⁴¹SO₂R⁴², —

B(OR⁴¹)(OR⁴²), —

P(O)(OR⁴¹)(OR⁴²) or —

P(O)(R⁴¹)(OR ⁴²);

R³⁷ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo, chloro, fluoro, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl —

CN, —

NO₂, —

OR⁴³, —

S(O)₁R⁴³, —

NR⁴³R⁴⁴, —

CONR⁴³R⁴⁴, —

CO₂R⁴³, —

SO₂NR⁴³R⁴⁴, —

NR⁴³SO₂R⁴⁴, —

B(OR⁴³)(OR⁴⁴), —

P(O)(OR⁴³)(OR⁴⁴) or —

P(O)(R⁴³)(OR⁴⁴);

R³⁸ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo, chloro, fluoro, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁴⁵, —

S(O)_mR⁴⁵, —

NR⁴⁵R⁴⁶, —

CONR⁴⁵R⁴⁶, —

CO₂R⁴⁵, SO₂NR⁴⁵R⁴⁶, —

NR⁴⁵SO₂R⁴⁶, —

B(OR⁴⁵)(OR⁴⁶), —

P(O)(OR⁴⁵)(OR⁴⁶) or —

P(O)(R⁴⁵)(OR⁴⁶);

j, k, I and m are independently 0, 1 or 2; and

R³⁹ —

R⁴⁶ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively R³⁹ and R⁴⁰, R⁴¹ and R⁴², R⁴³ and R⁴⁴ and R⁴⁵ R⁴⁶ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

with the proviso that at most, two of H, I, J and K are —

N—

.

62. The ligand modifier of claim 56 of structural Formula (IV):

wherein;

L is —

CHR⁶⁰—

, —

NR⁴⁷, —

O—

or—

S—

;

M is —

CHR⁶¹—

, —

NR⁴⁸, —

O—

or—

S—

;

R is —

CHR⁶²—

, —

NR⁴⁹, —

O—

or—

S—

;

T is —

CHR⁶³—

, —

NR⁵⁰, —

O—

or—

S—

;

o and p are independently 0 or 1;

R⁶⁰ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁶⁴, —

S(O)_tR⁶⁴, —

NR⁶⁴R⁶⁵, -—

CONR⁶⁴R⁶⁵, —

CO₂R⁶⁴, —

SO₂NR⁶⁴R⁶⁵, —

NR⁶⁴SO₂R⁶⁵, —

B(OR⁶⁴)(OR⁶⁵), —

P(O)(OR⁶⁴)(OR⁶⁵) or —

P(O)(R⁶⁴)(OR⁶⁵);

R⁶¹ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁶⁶, —

S(O)_uR⁶⁶, —

NR⁶⁶R⁶⁷, —

CONR⁶⁶R⁶⁷, —

CO₂R⁶⁶, —

SO₂NR⁶⁶R⁶⁷, —

NR⁶⁶SO₂R⁶⁷, —

B(OR⁶⁶)(OR⁶⁷), —

P(O)(OR⁶⁶)(OR⁶⁷) or—

P(O)(R⁶⁶)(OR⁶⁷);

R⁶² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁶⁸, —

S(O)_vR⁶⁸, —

NR⁶⁸R⁶⁹, —

CONR⁶⁸R⁶⁹, —

CO₂R⁶⁸, —

SO₂NR⁶⁸R⁶⁹, —

NR⁶⁸SO₂R⁶⁹, —

B(OR⁶⁸)(OR⁶⁹), —

P(O)(OR⁶⁸)(OR⁶⁹) or —

P(O)(R⁶⁸)(OR⁶⁹);

R⁶³ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁷⁰, —

S(O)_xR⁷⁰, —

NR⁷⁰R⁷¹, —

CONR⁷⁰R⁷¹, —

CO₂R⁷⁰, —

SO₂NR⁷⁰R⁷¹, —

NR⁷⁰SO₂R⁷¹, —

B(OR⁷⁰)(OR⁷¹), —

P(O)(OR⁷⁰)(OR⁷¹) or —

P(O)(R⁷⁰)(OR⁷¹);

t, u, v and x are independently 0, 1 or 2;

R⁶⁴—

R⁷¹ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively R⁶⁴ and R⁶⁵, R⁶⁶ and R⁶⁷, R⁶⁸ and R⁶⁹ and R⁷⁰ and R⁷¹ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and

R⁴⁷—

R⁵⁰ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;

with the provisos that that at most only one of L, M, R and T is a heteroatom.

63. The ligand modifier of claim 56, in which A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —

OR⁹, —

SR⁹, —

CN, —

NR⁹R¹⁰, —

CONR⁹R¹⁰, —

CO₂R⁹, —

NR⁹CO₂R¹⁰, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹ or —

NR⁹C(=NH)NR¹⁰R¹¹.

64. The ligand modifier of claim 56, in which A is —

OH, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

NHC(O)CH₃, —

NHC(O)OCH₃, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHC(NH)NH₂, —

CN, —

CH₂OH, —

CH₂NH₂, —

CH₂NHCH₃, —

CH₂N(CH₃)₂, —

CO₂H, —

CONH₂, —

CONHCH₃ or —

CH₂NHC(O)CH₃.

65. The ligand modifier of claim 56, in which D is —

OR¹⁵, —

S(O)_eR¹⁵, —

NR¹⁵NR¹⁶, —

CO₂R¹⁵, —

CONR¹⁵R¹⁶, C1, =N—

OR¹⁵ or =NHNHR¹⁵.

66. The ligand modifier of claim 56, in which D is —

OH, —

SH or —

NH₂.

67. The ligand modifier of claim 56, in which R¹⁷ is hydrogen, alkyl, substituted alkyl, arylalkyl, or substituted arylalkyl.

68. The ligand modifier of claim 56, in which R¹⁷ is hydrogen, —

CH₃, —

CH₂CH₃ or —

CH₂Ph.

69. The ligand modifier of claim 56, in which R¹² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —

OR¹³, —

SR¹³, —

CN, —

CONR¹³R¹⁴ or —

CO₂R¹².

70. The ligand modifier of claim 56, in which R¹² is hydrogen, —

OH, —

SH, —

CN, —

CH₂OH or —

CO₂H.

71. The ligand modifier of claim 56, in which A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —

OR⁹, —

SR⁹, —

CN, —

NR⁹R¹⁰, —

CONR⁹R¹⁰, —

CO₂R⁹, —

NR⁹CO₂R¹⁰, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹ or —

NR⁹C(=NH)NR¹⁰R¹¹, D is —

OR⁵, C1,  

S(O)_eR¹⁵, NR¹⁵NR¹⁶, —

CO₂R¹⁵ or —

CONR¹⁵R¹⁶ or D is =O, =S, =N—

OR¹⁵, =NHNHR¹⁵ and R¹² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —

OR¹³, —

SR¹³, —

CN, —

CONR¹³R¹⁴ or —

CO₂R¹³ .

72. The ligand modifier of claim 56, in which A is —

OH, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

NHC(O)CH₃, —

NHC(O)OCH₃, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHC(NH)NH₂, —

CN, —

CH₂OH, —

CH₂NH₂, —

CH₂NHCH₃, —

CH₂N(CH₃)₂, —

CO₂H, —

CONH₂, —

CONHCH₃, or —

CH₂NHC(O)CH₃, D is OH, SH or NH₂ or D is =O, =S, =N—

OR¹⁵ or =NHNHR¹⁵ and R¹² is hydrogen, —

OH, —

SH, —

CN, —

CH₂OH or —

CO₂H.

73. The ligand modifier of claim 56, in which A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —

OR⁹, —

SR⁹, —

CN, —

NR⁹R¹⁰, —

CONR⁹R¹⁰, —

CO₂R⁹, —

NR⁹CO₂R¹⁰, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹ or —

NR⁹C(=NH)NR¹⁰R¹¹ and R¹⁷ is hydrogen, alkyl, substituted alkyl, arylalkyl or substituted arylalkyl.

74. The ligand modifier of claim 56, in which A is —

OH, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

NHC(O)CH₃, —

NHC(O)OCH₃, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHC(NH)NH₂, —

CN, —

CH₂OH, —

CH₂NH₂, —

CH₂NHCH₃, —

CH₂N(CH₃)₂, —

CO₂H, —

CONH₂, —

CONHCH₃, or —

CH₂NHC(O)CH₃ and R¹⁷ is hydrogen, —

CH₃, —

CH₂CH₃ or —

CH₂Ph.

75. The ligand modifier of claim 56, in which A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —

OR⁹, —

SR⁹, —

CN, —

NR⁹R¹⁰, —

CONR⁹R¹⁰, —

CO₂R⁹, —

NR⁹CO₂R¹⁰, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹ or —

NR⁹C(=NH)NR¹⁰R¹¹, G is —

S(O)₂—

and R¹² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —

OR¹³, —

SR¹³, —

CN, —

CONR¹³R¹⁴ or —

CO₂R¹⁴.

76. The ligand modifier of claim 56, in which A is —

OH, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

NHC(O)CH₃, —

NHC(O)OCH₃, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHC(NH)NH₂, —

CN, —

CH₂OH, —

CH₂NH₂, —

CH₂NHCH₃, —

CH₂N(CH₃)₂, —

CO₂H, —

CONH₂, —

CONHCH₃, or —

CH₂NHC(O)CH₃, G is —

S(O)₂—

and R¹² is hydrogen, —

OH, —

SH, —

CN, —

CH₂OH or —

CO₂H.

77. The ligand modifier of claim 56, in which A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —

OR⁹, —

SR⁹, —

CN, —

NR⁹R¹⁰, —

CONR⁹R¹⁰, —

CO₂R⁹, —

NR⁹CO₂R¹⁰, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹ or —

NR⁹C(=NH)NR¹⁰R¹¹, G is —

S(O)₂—

and R¹⁷ is hydrogen, alkyl, substituted alkyl, arylalkyl or substituted arylalkyl.

78. The ligand modifier of claim 56 in which A is —

OH, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

NHC(O)CH₃, —

NHC(O)OCH₃, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHC(NH)NH₂, —

CN, —

CH₂OH, —

CH₂NH₂, —

CH₂NHCH₃, —

CH₂N(CH₃)₂, —

CO₂H, —

CONH₂, —

CONHCH₃, or —

CH₂NHC(O)CH₃, G is —

S(O)₂—

and R₁₇ is hydrogen, —

CH₃, —

CH₂CH₃ or —

CH₂Ph.

79. The ligand modifier of claim 60, in which W is —

S—

, NR²⁵, —

N—

—

O—

or —

C(R²⁴)—

, Y is —

CR²⁶—

and Z is —

S—

, —

NR²⁸—

, —

N—

, —

O—

or —

C(R²⁷)—

.

80. The ligand modifier of claim 60, in which W is —

C(R²⁴)—

, —

NR²⁵ or —

N—

, Y is —

N—

and Z is —

C(R²⁷)—

, —

NR²⁸ —

or—

N—

.

81. The ligand modifier of claim 60, in which A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —

OR⁹, —

SR⁹, —

CN, —

NR⁹R¹⁰, —

CONR⁹R¹⁰, —

CO₂R⁹, —

NR⁹CO₂R¹⁰, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹ or —

NR⁹C(=NH)NR¹⁰R¹¹, D is —

OR¹⁵, —

S(O)_eR¹⁵, C1, —

NR¹⁵NR¹⁶, —

CO₂R¹⁵ or —

CONR¹⁵R¹⁶ or D is =O, =S, =N—

OR¹⁵ or =NHNHR¹⁵ B is —

N—

, W is —

S—

, NR²⁵, —

N—

, —

O—

or —

C(R²⁵)—

, Y is —

CR²⁶—

and Z is —

S—

, —

NR<sup>28—

, —

N—

, —

O—

or —

C(R27</sup>)—

.

82. The ligand modifier of claim 60, in which A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —

OR⁹, —

SR⁹, —

CN, —

NR⁹R¹⁰, —

CONR⁹R¹⁰, —

CO₂R⁹, —

NR⁹CO₂R¹⁰, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹ or —

NR⁹C(=NH)NR¹⁰R¹¹, D is —

OR¹⁵, —

C1, S(O)_eR¹⁵, —

NR¹⁵NR¹⁶, —

CO₂R¹⁵ or —

CONR¹⁵R¹⁶, or D is =O, =S , =N—

OR¹⁵ or =NHNHR¹⁵, B is —

N—

, W is —

C(R )—

, —

NR²⁵ or —

N—

, Y is —

N—

and Z is —

C(R²⁷)—

, —

NR²⁸—

or —

N—

.

83. The ligand modifier of claim 60 of structural Formula (V):

wherein;

D is hydrogen, alkyl, aryl, halo, chloro, fluoro, —

OH, —

NH₂, —

SR⁵¹, —

CH₃, phenyl, —

CO₂H or —

CONH₂;

R⁵¹ is hydrogen, alkyl, substituted alkyl, arylalkyl, —

CH₃, —

CH₂CH₃, benzyl or —

CH₂CO₂C₂H₅;

A is —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

NHC(O)CH₃, —

NHC(O)OCH₃, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHC(NH)NH₂, —

CN, —

CH₂OH, —

CH₂NH₂, —

CH₂NHCH₃, —

CH₂N(CH₃)₂, —

CO₂H, —

CONH₂, —

CONHCH₃, or —

CH₂NHC(O)CH₃;

R⁵² is hydrogen, methyl, alkyl, —

CO₂R⁵⁴, —

CONR⁵⁴R⁵⁵, —

SO₂NR⁵⁴R⁵⁵, —

NR⁵⁴SO₂R⁵⁵, —

B(OR⁵⁴)(OR⁵⁵), —

P(O)(OR⁵⁴)(OR⁵⁵) or —

P(O)(R⁵⁴)(OR⁵⁵);

R⁵³ is hydrogen, alkoxy, alkyl, substituted alkyl, —

OCH₃, —

OC₂H₅, —

OC₃H₇, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, —

CH₂OH, —

CH₂OCH₃, —

CN, —

C(O)NR⁵⁶R⁵⁷, —

CO₂R⁵⁶, —

SO₂NR⁵⁶R⁵⁷, —

NR⁵⁶SO₂R⁵⁷, —

B(OR⁵⁶)(OR⁵⁷), —

P(O)(OR⁵⁶)(OR⁵⁷) or —

P(O)(R⁵⁶)(OR⁵⁷); and

R⁵⁴—

R⁵⁷ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively R⁵⁴ and R⁵⁵, R⁵⁶ and R⁵⁷, or R⁵² and R⁵³ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

provided that when R⁵² and R⁵³ are hydrogen then D is —

SH and A is -NH₂.

84. The ligand modifier of claim 83, wherein D is hydrogen, alkyl, aryl, —

OH, —

NH₂, —

CH₃, phenyl, —

CO₂H or —

CONH₂, R⁵¹ is alkyl, substituted alkyl, aryl alkyl, —

CH₃, —

CH₂CH₃, benzyl or —

CH₂CO₂C₂H₅, R⁵² is hydrogen, methyl, alkyl, —

CO₂R54, —

CONR⁵⁴R⁵⁵, —

SO₂NR⁵⁴R⁵⁵, —

NR⁵⁴SO₂R⁵⁵, —

B(OR⁵⁴)(OR⁵⁵), —

P(O)(OR⁵⁴)(OR⁵⁵) or —

P(O)(R⁵⁴)(OR⁵⁵) and R⁵³ is hydrogen, alkoxy, methyl, alkyl, substituted alkyl, —

OCH₃, —

OC₂H₅, —

OC₃H₇, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, —

CH₂OH, —

CH₂OCH₃, —

CN, —

C(O)NR⁵⁶R⁵⁷, —

CO₂R⁵⁶, —

SO₂NR⁵⁶R⁵⁷, —

NR⁵⁶SO₂R⁵⁷, —

B(OR⁵⁶)(OR⁵⁷), —

P(O)(OR⁵⁶)(OR⁵⁷) or —

P(O)(R⁵⁶)(OR⁵⁷).

85. The ligand modifier of claim 83, wherein when D is methyl, A is dimethylamino and R⁵³ is hydrogen then R⁵² is not methyl, ethyl or carboxyl;

when D is methyl, A is dimethylamino and R⁵³ is methyl then R⁵² is not methyl;

when D is —

SCH₃, A is dimethylamino and R⁵³ is hydrogen then R⁵² is not carboethoxy;

when D is hydrogen, A is dimethylamino and R⁵³ is hydrogen then R⁵² is not carboxyl or carboethoxy;

when D is hydrogen, A is dimethylamino and R⁵³ is methyl then R⁵² is not methyl;

when D is hydrogen, A is methylamino and R⁵³ is hydrogen then R⁵² is not methyl, ethyl or carboethoxy;

when D is hydrogen, A is methylamino and R⁵³ is methyl then R⁵² is not methyl or carboethoxy;

when D is hydrogen, A is methylamino and R⁵³ is —

CH₂NMe then R⁵² is not methyl or carboethoxy;

when D is phenyl, A is methylamino and R⁵³ is hydrogen then R⁵² is not methyl;

when D is phenyl, A is —

NH(CO)CH₃ and R⁵³ is methyl then R⁵² is not carbomethoxy.

86. The ligand modifier of claim 60 of structural formula (VI):

wherein D is hydrogen, —

CH₃, —

C₂H₅, phenyl or benzyl.

87. The ligand modifier of claim 60 of structural formula (VII):

wherein A is hydrogen, —

CH₃, —

C₂H₅, phenyl or benzyl.

88. The ligand modifier of claim 60 of structural formula (VIII):

wherein R⁹ and R¹⁰ are independently hydrogen, —

CH₃, —

C₂H₅, phenyl or benzyl provided that both R⁹ and R¹⁰ are not hydrogen.

89. The ligand modifier of claim 83 of structural formula (IX):

wherein R⁵² is —

OCH₃, —

OC₂H₅, —

OC₃H₇, —

C₂H₅, —

CH(CH₃)₂, —

CH₂OH, —

CH₂OCH₃, —

CN, —

C(O)NR⁵⁴R⁵⁵, —

CO₂R⁵⁴, —

SO₂NR⁵⁴R⁵⁵, —

NR⁵⁴SO ₂R⁵⁵, —

B(OR⁵⁴)(OR⁵⁵), —

P(O)(OR⁵⁴)(OR⁵⁵), —

P(O)(R⁵⁴)(OR⁵⁵) or substituted alkyl;

R⁵³ is methyl, alkyl, CO₂R⁵⁶ or —

CONR⁵⁶ R⁵⁷, —

SO₂NR⁵⁶R⁵⁷, —

NR⁵⁶SO₂R⁵⁷, —

B(OR ⁵⁶)(OR⁵⁷), —

P(O)(OR )(OR⁵⁶) or —

P(O)(R⁵⁶)(OR⁵⁷); and

R⁵⁴—

R⁵⁷ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively R⁵⁴ and R⁵⁵, R⁵⁶ and R⁵⁷, or R⁵² and R⁵³ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

90. The ligand modifier of claim 60 of structural formula (X):

wherein D is —

OH, —

SH or —

NH₂, R⁵² is —

OCH₃, —

OC₂H₅,OC₃H₇, —

C₂H₅, —

CH(CH₃)₂, 13 CH₂OH, —

CH₂OCH₃, —

CN, —

C(O)NR⁵⁴R⁵⁵, —

CO₂R⁵⁴ or substituted alkyl, R⁵² is —

OCH₃, —

OC₂H₅, —

OC₃H₇, —

C₂H₅, —

CH(CH₃)₂, —

CH₂OH, —

CH₂OCH₃, —

CN, —

C(O)NR⁵⁴R⁵⁵, —

CO₂R⁵⁴, —

SO₂NR⁵⁴R⁵⁵, —

NR⁵⁴SO₂R⁵⁵, —

B(OR⁵⁴)(OR⁵⁵), —

P(O)(OR⁵⁴)(OR⁵⁵), —

P(O)(R⁵⁴)(OR⁵⁵) or substituted alkyl and R⁵⁴ and R⁵⁵ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively R⁵⁴ and R⁵⁵ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

91. The ligand modifier of claim 60 having the structure:

wherein R⁵¹ is —

CH₃, —

CH₂CH₃, benzyl or —

CH₂CO₂CH₂CH₃.

92. The ligand modifier of claim 60 having the structure:

93. The ligand modifier of claim 60 having the structure:

94. The ligand modifier of claim 60 having the structure:

95. The ligand modifier of claim 60, having the structure:

96. The ligand modifier of claim 60, having the structure:

wherein R is —

OH, —

SH, —

CN, —

CH₂OH or —

CO₂H.

97. The ligand modifier of claim 60 having the structure:

98. The ligand modifier of claim 60 having the structure:

99. The ligand modifier of claim 60 having the structure:

100. The ligand modifier of claim 61, wherein H is —

C(R³⁵)—

or—

N—

;

I is —

C(R³⁶)—

;

J is —

C(R³⁷)—

; and

K is —

C(R³⁸)—

or—

N—

.

101. The ligand modifier of claim 61, in which A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —

OR¹, —

CN, —

NR⁹R¹⁰, —

CONR⁹R¹⁰, —

CO₂R⁹, —

NR⁹CO₂R¹⁰, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹ or —

NR⁹C(=NH)NR¹⁰R¹¹, D is —

OR¹⁵, —

NOR¹⁵, —

S(O)_eR¹⁵, —

NR¹⁵NR¹⁶, —

CO₂R¹⁵ or—

CONR¹⁵R¹⁶ or D is =O, =S, =N—

OR¹⁵, B is —

N—

, H is -—

(R³⁵)—

or —

N—

, I is —

C(R³⁶)—

, J is —

C(R³⁷)—

and K is —

C(R³⁸)—

or—

N—

.

102. The ligand modifier of claim 61 of structural Formula (XI):

wherein R¹² is hydrogen, —

OH, —

SH, —

CN, —

CH₂OH or —

CO₂H;

D is —

OH or —

SH;

A is —

OH, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

NHC(O)CH₃, —

NHC(O)OCH₃, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHC(NH)NH₂, —

CN, —

CH₂OH, —

CH₂NH₂, —

CH₂NHCH₃, —

CH₂N(CH₃)₂, —

CO₂H, —

CONH₂, —

CONHCH₃, or —

CH₂NHC(O)CH₃;

R³⁵ is hydrogen, alkoxy, —

OCH₃, —

OC₂H₅, —

OC₃H₇, alkyl, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, halo, chioro, fluoro, —

CH₂OH, —

CH₂OCH₃, —

CN, —

C(O)NR³⁹R⁴⁰, —

CO₂R⁴⁰, —

SO₂NR³⁹R⁴⁰, —

NR³⁹SO₂R⁴⁰, —

B(OR³⁹)(OR⁴⁰), —

P(O)(OR³⁹)(OR⁴⁰) or—

P(O)(R³⁹ )(OR⁴⁰ );

R³⁶ is hydrogen, alkoxy, —

OCH₃, —

OC₂H₅, —

OC₃H₇, alkyl, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, halo, chloro, fluoro, —

CH₂OH, —

CH₂OCH₃, —

CN, —

C(O)NR⁴¹R⁴², CO₂R⁴¹, —

SO₂NR⁴¹R⁴², —

NR⁴¹SO₂R⁴², —

B(OR⁴¹)(OR⁴²), —

P(O)(OR⁴¹)(OR⁴²) or —

P(O)(R⁴¹)(OR⁴²);

R³⁷ is hydrogen, alkoxy, —

OCH₃, —

OC₂H₅, —

OC₃H7, alkyl, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, halo, chloro, fluoro, —

CH₂OH, —

CH₂OCH₃, —

CN, —

C(O)NR⁴³R⁴⁴, —

CO₂R⁴³, —

SO₂NR⁴³R⁴⁴, —

NR⁴³SO₂R⁴⁴, —

B(OR⁴³)(OR⁴⁴), —

P(O)(OR⁴³)(OR⁴⁴) or —

P(O)(R⁴³)(OR⁴⁴);

R³⁸ is hydrogen, alkoxy, —

OCH₃, —

OC₂H₅, —

OC₃H₇, alkyl, —

CH₃, —

C₂H₅, -CH(CH3)2, halo, chioro, fluoro, -CH2OH, -CH2OCH3, -CN, -C(O)NR R , -CO2R -S02NR45R46, -NR45S02R46, -B(0R45)(0R46), -P(O)(0R45)(0R46) or and

R³⁹—

R⁴⁶ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively R³⁹ and R⁴⁰, R⁴¹ and R⁴², R⁴³ and R⁴⁴ and R⁴⁵ and R⁴⁶ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

provided that when R¹² is hydrogen then R³⁶, R³⁷, R³⁸ and R³⁹ are not hydrogen.

103. The ligand modifier of claim 102, wherein R¹² is —

OH, —

SH, —

CN, —

CH₂OH or —

CO₂H and A is —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

NHC(O)CH₃, —

NHC(O)OCH₃, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHC(NH)NH₂, —

CN, —

CH₂OH, —

CH₂NH₂, —

CH₂NHCH₃, —

CH₂N(CH₃)₂, —

CO₂H, —

CONH₂, —

CONHCH₃, or —

CH₂NHC(O)CH₃.

104. The ligand modifier of claim 103, wherein when R³⁶, R³⁷, R³⁸ and R³⁹ are hydrogen, D is —

OH and A is —

CO₂H then R¹² not —

CO₂H or —

OH;

when R³⁶, R³⁷, R³⁸ and R³⁹ are hydrogen, D is —

OH and A is —

NH₂ then R¹² is not —

CO₂H or CN;

when R³⁶, R³⁸ and R³⁹ are hydrogen, R³⁷ is —

OMe, D is —

OH and A is —

CH₂OH then R¹² not —

CH₂OH;

when R³⁶, R³⁸ and R³⁹ are hydrogen, R³⁷ is hydrogen or methyl, D is —

OH and A is —

CO₂H then R¹² not —

SH.

105. The ligand modifier of claim 61 of Formula (XII):

wherein R¹² is hydrogen, —

OH, —

SH, —

CN, —

CH₂OH or —

CO₂H;

D is —

SH or —

OH;

A is —

OH, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

NHC(O)CH₃, —

NHC(O)OCH₃, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHC(NH)NH₂, —

CN, —

CH₂OH, —

CH₂NH₂, —

CH₂NHCH₃, —

CH₂N(CH₃)₂, —

CO₂H, —

CONH₂, —

CONHCH₃, or —

CH₂NHC(O)CH₃;

R₃₆ is hydrogen, —

OCH₃, —

OC₂H₅, —

OC₃H₇, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, —

CH₂OH, —

CH₂OCH₃, —

CN, —

C(O)NR⁴¹R⁴², —

CO₂R⁴¹, —

SO₂NR³⁹R⁴⁰, —

NR³⁹SO₂R⁴⁰, —

B(OR³⁹)(OR⁴⁰), —

P(O)(OR³⁹)(OR⁴⁰) or —

P(O)(R³⁹)(OR⁴⁰);

R³⁷ is hydrogen, —

OCH₃, —

OC₂H₅, —

OC₃H₇, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, —

CH₂OH, —

CH₂OCH₃, —

CN, —

C(O)NR⁴³R⁴⁴, —

CO₂R⁴³, —

SO₂NR⁴³R⁴⁴, NR⁴³SO₂R⁴⁴, —

B(OR⁴³)(OR⁴⁴), —

P(O)(OR⁴³)(OR⁴⁴) or —

P(O)(R⁴³)(OR⁴⁴); and

R⁴¹—

R⁴⁴ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively R⁴¹ and R⁴² and R⁴³ and R⁴⁴ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

106. The ligand modifier of claim 105, wherein R¹² is —

OH, —

SH, —

CN, —

CH₂OH or —

CO₂H;

107. The ligand modifier of claim 61 of structural Formula (XIII):

wherein;

D is =O or =S;

A is —

OH, NH₂, —

NHCH₃, —

N(CH₃)₂, —

NHC(O)CH₃, —

NHC(O)OCH₃, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHC(NH)NH₂, —

CN, —

CH₂OH, —

CH₂NH₂, —

CH₂NHCH₃, —

CH₂N(CH₃)₂, —

CO₂H, —

CONH₂, —

CONHCH₃, or —

CH₂NHC(O)CH₃;

R¹⁷ is alkyl or aryl;

R³⁵ is hydrogen, alkoxy, —

OCH₃, —

OC₂H₅, —

OC₃H₇, alkyl, —

CH₃, C₂H₅, —

CH(CH₃)₂, —

CH₂OH, halo, chloro, fluoro, —

CH₂OCH₃, —

CN, —

NR³⁹R⁴⁰, —

C(O)N³⁹R⁴⁰ , —

CO₂R⁴⁰, —

SO₂NR³⁹R⁴⁰, —

NR³⁹SO₂R⁴, —

B(OR³⁹)(OR⁴⁰), —

P(O)(OR³⁹)(OR⁴⁰) or —

P(O)(R³⁹)(OR⁴⁰);

R³⁶ is hydrogen, —

OCH₃, —

OC₂H₅, —

OC₃H₇, alkoxy, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, —

CH₂OH, halo, chloro, fluoro, —

CH₂OCH₃, —

CN, —

NR⁴¹R⁴¹, —

C(O)NR⁴¹R⁴², —

CO₂R⁴¹, —

SO₂NR⁴¹R⁴², —

NR⁴¹SO₂R⁴², —

B(OR⁴¹)(OR⁴²), —

P(O)(OR⁴¹)(OR⁴²) or —

P(O)(R⁴¹)(OR⁴²);

R³⁷ is hydrogen, —

OCH₃, —

OC₂H₅, —

OC₃H₇, alkoxy, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, alkyl, —

CH₂OH, halo, chloro, fluoro, —

CH₂OCH₃, —

CN, —

NR⁴³R⁴⁴, —

C(O)NR⁴³R⁴⁴, —

CO₂R⁴³, —

SO₂NR⁴³R⁴⁴, —

NR⁴³SO₂R⁴⁴, —

B(OR⁴³)(OR⁴⁴), —

P(O)(OR⁴³)(OR⁴⁴) or —

P(O)(R⁴³)(OR⁴⁴);

R³⁸ is hydrogen, —

OCH₃, —

OC₂H₅, —

OC₃H₇, alkoxy, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, alkyl, —

CH₂OH, halo, chloro, fluoro, —

CH₂OCH₃, —

CN, —

NR⁴⁵R⁴⁶, —

C(O)NR⁴⁵R⁴⁶, —

CO₂R⁴⁵, SO₂NR⁴⁵R⁴⁶, —

NR⁴⁵SO₂R⁴⁶, —

B(OR⁴⁵)(OR⁴⁶), —

P(O)(OR⁴⁵)(OR⁴⁶) or —

P(O)R⁴⁵)(OR⁴⁶); and

R³⁹R⁴⁶ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively R³⁹ and R⁴⁰, R⁴¹ and , R⁴², R⁴³ and R⁴⁴ and R⁴⁵ and R⁴⁶ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

108. The ligand modifier of claim 107, wherein when A is =O, A is —

NH₂ and R³⁵, R³⁶, R³⁷ and R³⁸ are hydrogen then R¹⁷ is not methyl, ethyl or phenyl.

109. The ligand modifier of claim 61 of structural Formula (XIV):

wherein;

A is —

OH, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

NHC(O)CH₃, —

NHC(O)OCH₃, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHC(NH)NH₂, —

CN, —

CH₂OH, —

CH₂NH₂, —

CH₂NHCH₃, —

CH₂N(CH₃)₂, —

CO₂H, —

CONH₂, —

CONHCH₃, or —

CH₂NHC(O)CH₃;

R¹⁷ is alkyl or aryl;

R³⁶ is hydrogen, —

OCH₃, —

OC₂H₅, —

OC₃H₇, —

C₂H₅, —

CH(CH₃)₂, —

CH₂OH, —

CH₂OCH₃, —

CN, —

NR⁴¹R⁴², —

C(O)NR⁴¹R⁴², —

CO₂R⁴¹, —

SO₂NR⁴¹R⁴², —

NR⁴¹SO₂R⁴², —

B(OR⁴¹)(OR⁴²), —

P(O)(OR⁴¹)(OR⁴²) or —

P(O)(R⁴¹)(OR⁴²);

R³⁷ is hydrogen, —

OCH₃, —

OC₂H₅, —

OC₃H₇, —

C₂H₅, —

CH(CH₃)₂, —

CH₂OH, —

CH₂OCH₃, —

CN, —

NR⁴³R⁴⁴, —

C(O)NR⁴³R⁴⁴, —

CO₂R⁴³, —

SO₂NR⁴³R⁴⁴, —

NR⁴³SO₂R⁴⁴, —

B(OR⁴³) (OR⁴⁴), —

P(O)(OR⁴³)(OR⁴²) or —

P(O)(R⁴³)(OR⁴⁴); and

R³⁹—

R⁴⁴ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively R⁴¹ and R⁴² and R⁴³ and R⁴⁴ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

110. The ligand modifier of claim 109, wherein when R³⁶ and R³⁷ are methyl, D is =O and A is —

NH₂ then R¹⁷ not methyl.

111. The ligand modifier of claim 61 having the structure:

112. The ligand modifier of claim 61 having the structure:

113. The ligand modifier of claim 61 having the structure:

114. The ligand modifier of claim 61, having the structure:

115. The ligand modifier of claim 61, having the structure:

116. The ligand modifier of claim 61, having the structure:

117. The ligand modifier of claim 61, having the structure:

118. The ligand modifier of claim 62, in which L, R and T are —

CH₂—

, o and p are 1 and M is —

N(R⁴⁸)—

, —

S—

or —

O—

and R⁴⁸ is hydrogen, —

CH₃ or —

COCH₃.

119. The ligand modifier of claim 62, in which A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —

OR¹, —

SR¹, —

CN, —

NR⁹R¹⁰, —

CONR⁹R¹⁰, —

CO₂R⁹, —

NR⁹CO₂R¹⁰, —

NR⁹CONR¹⁰R¹¹, —

NR⁹CSNR¹⁰R¹¹ or —

NR⁹C(=NH)NR¹⁰R¹¹, D is —

OR¹⁵, —

NOR¹⁵, —

S(O)_eR¹⁵, —

NR¹⁵NR¹⁶, —

CO₂R¹⁵ or —

CONR¹⁵R¹⁶ or D is =O, =S, =N—

OR¹⁵, B is —

N—

, L, R and T are —

CH₂—

, o and p are 1 and M is —

N(R⁴⁸)—

, —

S—

or —

O—

and R⁴⁸ is hydrogen, —

CH₃ or —

COCH₃.

120. The ligand modifier of claim 62, having the structure:

wherein;

D is —

SH or —

OH; and

A is —

OH, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

NHC(O)CH₃, —

NHC(O)OCH₃, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHC(NH)NH₂, —

CN, —

CH₂OH, —

CH₂NH₂, —

CH₂NHCH₃, —

CH₂N(CH₃)₂, —

CO₂H, —

CONH₂, —

CONHCH₃, or —

CH₂NHC(O)CH₃;

provided that at least one of L, M, T or R is a heteroatom.

121. The ligand modifier of claim 120, wherein when p is 0, L is —

NH—

, M is —

CH(CH₂OEt)—

, R is

X is hydrogen, chloro or methoxy, A is —

NH₂ then D is not —

SH;

when p is 0, L is —

CH₂—

, M is —

NCH₃—

, R is —

C(CH₃)₂—

, A is —

NH₂, then D is not —

SH or —

OH;

when p is 0, L is —

NH—

, M is —

CH(CH₂OH)—

, R is

X is hydrogen or methoxy, A is —

NH₂

then D is not —

SH;

when p is 0, L is —

NH—

, M is —

CH(CH₃)—

, R is

A is -NH₂ then D is not —

SH;

L is —

S—

, M, R and T are —

CH₂—

, A is —

NH₂ then D is not —

OH;

L is —

NH—

, M and T are —

CH₂—

, R is —

CH(CH₃)—

, A is —

NH₂ then D is not —

OH; and

M is —

N(COPh)—

, L, R and T are —

CH₂—

, A is —

NH₂ then D is not —

OH.

122. The ligand modifier of claim 62 having the structure:

123. The chemosensory receptor ligand modifier of claim 52, wherein it is a chemosensory receptor ligand enhancer and has the structural Formula (XVI):

or a salt, solvate, hydrate or N-oxide thereof wherein;

each G is independently —

C(R⁷⁷)(R⁷⁹)—

, —

C(O)—

, —

NR⁷⁷ —

or—

S(O)₂—

;

n is 1, 2 or 3;

provided that when n is greater than one then only one G is —

C(O)—

, —

C(S), —

S(O)₂—

or—

NR⁷⁷—

;

Y is —

C(O)—

, —

C(S) or —

S(O)₂—

;

R⁷⁰ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁷², —

S(O)_aR⁷², —

NR⁷²R⁷³, —

CONR⁷²R⁷³, —

CO₂R⁷², —

NR⁷²CO₂R⁷³, —

NR⁷²CONR⁷³R⁷⁴, —

NR⁷²CSNR⁷³R⁷⁴ or—

NR⁷²C(=NH)NR⁷³R⁷⁴, —

SO₂NR⁷²R⁷³, —

NR⁷²SO₂R⁷³, —

NR⁷²SO₂NR⁷³R⁷⁴, —

B(OR⁷²)(OR⁷³), —

P(O)(OR⁷²)(OR⁷³) or—

P(O)(R⁷²)(OR⁷³);

R⁷¹ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁷⁴, —

S(O)_bR⁷⁴, —

NR⁷⁴R⁷⁵, —

CONR⁷⁴R⁷⁵, —

CO₂R⁷⁴, —

NR⁷⁴CO₂R⁷⁵, —

NR⁷⁴CONR⁷⁵R⁷⁶, —

NR⁷⁴CSNR⁷⁵R⁷⁶ or—

NR⁷⁴C(=NH)NR⁷⁵R⁷⁶, —

SO₂NR⁷⁴R⁷⁵, —

NR⁷⁴SO₂R⁷⁵, —

NR⁷⁴SO₂NR⁷⁵R⁷⁶, —

B(OR⁷⁴)(OR⁷⁵), —

P(O)(OR⁷⁴)(OR⁷⁵), —

P(O)(R⁷⁴)(OR⁷⁵) or alternatively, R⁷¹ and R⁷² together with the atoms to which they are bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring where the ring is optionally fused to another aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

a and b are independently, 0, 1 or 2;

R⁷²—

R⁷⁶ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R⁷² and R⁷³, R⁷³ and R⁷⁴, R⁷⁴ and R⁷⁵ and R⁷⁵ and R⁷⁶ together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and

are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R⁷⁷ and R⁷⁸, together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring.

124. The ligand modifier of claim 123, wherein when G is —

C(O)—

, and R⁷⁸ is hydrogen, R⁷¹ and R⁷² do not form a phenyl ring.

125. The ligand modifier of claim 123, wherein R⁷⁰ and R⁷¹ together with the atoms to which they are bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring where the ring is optionally fused to another aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring.

126. The ligand modifier of claim 123 of structural formula (XVII), (XVIII), (XIX) or (XX):

where o is 1 or 2.

127. The ligand modifier of claim 126, wherein R⁷⁰ and R⁷¹ together with the atoms to which they are bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring where the ring is optionally fused to another aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring.

128. The ligand modifier of claim 123 of structural formula (XXI):

wherein;

X is O or S;

H is —

N—

or—

CR⁸¹—

;

I is —

N—

or—

CR⁸²—

;

J is —

N—

or—

CR⁸³—

;

K is —

N13 or—

CR⁸⁴—

;

with the proviso that no more than 2 of H, I ,J or K are —

N—

;

R⁸¹ is hydrogen, alkoxy, —

OCH₃, —

OC₂H₅, —

OC₃H₇, alkyl, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, —

CH₂OH, halo, chloro, fluoro, —

CH₂OCH₃, —

CN, —

C(O)NR⁸⁵R⁸⁶, —

CO₂R⁸⁵, —

SO₂NR⁸⁵R⁸⁶, —

NR⁸⁵SO₂R⁸⁶, —

B(OR⁸⁵)(OR⁸⁶), —

P(O)(OR⁸⁵)(OR⁸⁶) or—

P(O)(R⁸⁵)(OR⁸⁶);

R⁸² is hydrogen, alkoxy, —

OCH₃, —

OC₂H₅, —

OC₃H₇, alkyl, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, —

CH₂OH, halo, chloro, fluoro, —

CH₂OCH₃, —

CN, —

C(O)NR⁸⁶R⁸⁷, —

CO₂R⁸⁶, —

SO₂NR⁸⁶R⁸⁷, —

NR⁸⁶SO₂R⁸⁷, —

B(OR⁸⁶)(OR⁸⁷), —

P(O)(OR⁸⁶)(OR⁸⁷) or—

P(O)R⁸⁶)(OR⁸⁷);

R⁸³ is hydrogen, alkoxy, —

OCH₃, —

OC₂H₅, —

OC₃H₇, alkyl, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, —

CH₂OH, halo, chloro, fluoro, —

CH₂OCH₃, —

CN, —

C(O)NR⁸⁸R⁸⁹, —

CO₂R⁸⁸, —

SO₂NR⁸⁸R⁸⁹, —

NR⁸⁸SO₂R⁸⁹, —

B(OR⁸⁸)(OR⁸⁹), —

P(O)(OR⁸⁸)(OR⁸⁹) or—

P(O)(R⁸⁸)(OR⁸⁹);

R⁸⁴ is hydrogen, alkoxy, —

OCH₃, —

OC₂H₅, —

OC₃H₇, alkyl, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, halo, chloro, fluoro, —

CH₂OH, —

CH₂OCH₃, —

CN, —

C(O)NR⁹⁰R⁹¹, —

CO₂R⁹⁰, —

SO₂NR⁹⁰R⁹¹, —

NR⁹⁰SO₂R⁹¹, —

B(OR⁹⁰)(OR⁹¹), —

P(O)(OR⁹⁰)(OR⁹¹) or —

P(O)(R⁹⁰)(OR⁹¹); and

R⁸⁵—

R⁹¹ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively R⁸⁵ and R⁸⁶, R⁸⁷ and R⁸⁸, R⁸⁹ and R⁹⁰ and R⁹¹ and R⁹² together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

provided that R⁸¹, R⁸², R⁸³ and R⁸⁴ are not all hydrogen.

129. The ligand modifier of claim 128, wherein R⁸¹, R⁸², R⁸³ and R⁸⁴ are independently hydrogen, —

OCH₃, —

OC₂H₅, —

OC₃H₇, alkyl, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, —

CH₂OH, halo, chloro, fluoro, —

CH₂OCH₃, —

CN, —

C(O)NHMe, —

CO₂H, —

CO₂CH₃, —

SO₂N(CH₃)₂, —

NHSO₂CH₃, —

B(OH)₂ or—

P(O)(OH)₂.

130. The ligand modifier of claim 123 having the structure:

131. The ligand modifier of claim 52, wherein it is a chemosensory receptor ligand enhancer and has the structural Formula (XXII):

or a salt, solvate, hydrate or N-oxide thereof wherein;

each G is independently —

C(R⁹⁴)(R⁹⁵)—

, —

C(O)—

, —

NR⁹⁴—

or—

S(O)₂—

;

n is 1, 2 or 3;

provided that when n is greater than one then only one G is —

C(O)—

, —

S(O)₂—

or—

NR⁹⁴—

;

Y is —

C(O)—

, —

C(S)—

or—

S(O)₂—

;

L is —

C(R¹⁰⁴)(R¹⁰⁵)—

, —

O—

, or—

NR¹⁰⁴—

;

R⁹² is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR⁹⁸, —

S(O)_yR⁹⁸, —

NR⁹⁸R⁹⁹, —

CONR⁹⁸R⁹⁹, —

CO₂R , —

NR⁹⁸CO₂R⁹⁹, —

NR⁹⁸CONR⁹⁹R¹⁰⁰, —

NR⁹⁸CSNR⁹⁹R¹⁰⁰ or—

NR⁹⁸C(=NH)NR⁹⁹R¹⁰⁰, —

SO₂NR⁹⁸R⁹⁹, —

NR⁹⁸SO₂R⁹⁹, —

NR⁹⁸SO₂NR⁹⁹R¹⁰⁰, —

B(OR⁹⁸)(OR⁹⁹), —

P(O)(OR⁹⁸)(OR⁹⁹) or—

P(O)(R⁹⁸)(OR⁹⁹);

R⁹³ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —

CN, —

NO₂, —

OR¹⁰¹, —

S(O)_zR¹⁰¹, —

NR¹⁰¹R¹⁰², —

CONR¹⁰¹R¹⁰², —

CO₂R¹⁰¹, —

NR¹⁰¹CO₂R¹⁰², —

NR¹⁰¹CONR¹⁰²R¹⁰³, —

NR¹⁰¹CSNR¹⁰²R¹⁰³ or—

NR¹⁰¹C(=NH)NR¹⁰²R¹⁰³, —

SO₂NR¹⁰¹R¹⁰², —

NR¹⁰¹SO₂R¹⁰², NR¹⁰¹SO₂NR¹⁰²R¹⁰³, —

B(OR¹⁰¹)(OR¹⁰²), —

P(O)(OR¹⁰¹)(OR¹⁰²), —

P(O)(R¹⁰¹)(OR¹⁰²) or alternatively, R⁹² and R⁹³ together with the atoms to which they are bonded form an aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring where the ring is optionally fused to another aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

y and z are independently 0, 1 or 2;

R⁹⁸—

R¹⁰³ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R⁹⁸ and R⁹⁹, R⁹⁹ and R¹⁰⁰, R¹⁰¹ and R¹⁰² and R¹⁰¹ and R¹⁰² together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

R⁹⁴—

R⁹⁵ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R⁹⁴ and R⁹⁵, together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

R⁹⁶ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and

R¹⁰⁴—

R¹⁰⁵ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R¹⁰⁴ and R¹⁰⁵, together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring.

132. The ligand modifier of claim 131, wherein when L is O, R⁹⁵ is hydrogen, R⁹² is methyl and the bond connecting the carbon atoms bonded to R⁹² and R⁹³ is a double bond then R⁹³ is not hydrogen.

133. The ligand modifier of claim 131 of structural formula (XXIII):

provided that when R⁹² is —

CH₃ then R⁹³ is not R⁹² and R⁹³ are not hydrogen.

134. The ligand modifer of claim 133, wherein R⁹² and R⁹³ are independently hydrogen, —

OCH₃, —

OC₂H₅, —

OC₃H₇, alkyl, —

CH₃, —

C₂H₅, —

CH(CH₃)₂, —

CH₂OH, halo, chloro, fluoro, —

CH₂OCH₃, —

CN, —

SCH₃, —

C(O)NHMe, —

CO₂H, —

CO₂CH₃, —

SO₂N(CH₃)₂, —

NHSO₂CH₃, —

B(OH)₂ or —

P(O)(OH)₂.

135. The ligand modifier of claim 131 having the structure:

136. The chemosensory receptor ligand modifier of claim 52 in a comestible composition.

137. The chemosensory receptor ligand modifier of claim 52 in a food or beverage product.

138. The chemosensory receptor ligand modifier of claim 52 in a medicinal composition as a non-active ingredient.

139. The chemosensory receptor ligand modifier of claim 52 in a medicinal composition as an active ingredient.

140. A comestible composition comprising between about 0.0001 ppm to about 10 ppm of a ligand modifier of any one of claims 56, 123, and 131.

141. A comestible or medicinal composition comprising between about 0.01 ppm to about 100 ppm of a ligand modifier of any one of claims 56, 123, and 131 and at least a sweet flavor entity.

142. A composition comprising between about 10 ppm to about 100,000 ppm of a ligand modifier of any one of claims 56, 123, and 131.

143. A method of enhancing the sweet taste of a comestible or medicinal product comprising contacting a comestible or medicinal product or precursors thereof with a ligand modifier of any one of claims 56, 123 and 131 to form a modified comestible or medicinal product, wherein the modified comestible or medicinal product comprises at least about 0.001 ppm of the compound.

144. The method of claim 143 wherein the modified comestible or medicinal product comprises at least between about 0.001 ppm to about 100,000 ppm of the ligand modifier.

145. A method of treating a condition associated with a chemosensory receptor comprising administering to a subject in need of such treatment an effective amount of an entity selected from the group consisting of a chemosensory receptor modifier, chemosensory receptor ligand modifier, and a combination thereof, wherein the entity interacts with an interacting site of the chemosensory receptor.

146. The method of claim 145, wherein the condition associated with a chemosensory receptor is taste.

147. The method of claim 145, wherein the condition associated with a chemosensory receptor is a condition associated with gastrointestinal system or metabolic disorders.

148. The method of claim 145, wherein the condition associated with a chemosensory receptor is a condition associated with a functional gastrointestinal disorder.

149. The method of claim 145, wherein the condition associated with a chemosensory receptor is a condition associated with cells expressing a T1R.

150. The method of claim 145, wherein the condition associated with a chemosensory receptor is a condition associated with hormone-producing cells that express a T1R.