DRUG DISCOVERY METHOD

• US 20110237458A1
• Filed: 06/06/2011
• Published: 09/29/2011
• Est. Priority Date: 07/24/2002
• Status: Active Grant

• Current Assignee: Keddem Bioscience Ltd. (Compugen Ltd)
• Original Assignee: Keddem Bioscience Ltd. (Compugen Ltd)
• Inventors: OFER, Dror
• Granted Patent: US 9,405,885 B2
• Time in Patent Office: Days
• US Class Current: 506/9
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12Q 1/68 involving nucleic acids
• CPC Class Codes: C40B 30/04 by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
• CPC Class Codes: C40B 40/00 Libraries per se, e.g. arrays, mixtures
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 33/53 Immunoassay; Biospecific binding assay; Materials therefor
• 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 15/30 Drug targeting using structural data; Docking or binding prediction
• CPC Class Codes: G16B 45/00 ICT specially adapted for bioinformatics-related data visualisation, e.g. displaying of maps or networks
• CPC Class Codes: G16C 20/50 Molecular design, e.g. of drugs
• CPC Class Codes: G16C 20/70 Machine learning, data mining or chemometrics

Abstract

A method of obtaining information about a chemically active area of a target molecule, for example for drug discovery, comprising:

• • providing a set of substantially rigid chemical gauges;
  • reacting said target with a plurality of gauges of said set of gauges;
  • assaying a binding of said gauges with said target to obtain a plurality of assay results; and
  • analyzing said assay results to obtain information about said chemically active area.

Claims

1. A set of substantially rigid chemical gauges, each of said gauges being a compound comprising at least one set of three binding points in a substantially rigid triangular configuration,

such that for a triangle space which defines all possible 3-point pharmacophores defined by a triplet of distances that form a triangle, each distance being in a range of 2-12 angstrom, and by a triplet of chemical binding point types for the triangle vertices, each chemical binding point type being selected from the group consisting of acid, base, hydrophobic, hydrogen-bond donor, hydrogen-bond acceptor, and aromatic:

for each point in 50% of said triangle space, said set of gauges comprises at least six gauges with a substantially rigid triangular configuration of binding points capable of chemically binding to a 3-point pharmacophore corresponding to said point.

2. A gauge set according to claim 1, wherein said gauges comprise chemical moieties at said binding points, said moieties being capable of rotation.

3. A gauge set according to claim 1, wherein said gauges are constructed using a rigid scaffold.

4. A gauge set according to claim 3, in which the gauge molecules are composed of said rigid scaffold and chemical moieties, each of said moieties being attached to said scaffold via one rotationally free bond.

5. A gauge set according to claim 3, wherein said rigid scaffold contains no rotationally free bonds between any two atoms in said scaffold.

6. A gauge set according to claim 1, wherein constituent atoms of said gauges do not move more than 1 Å

unless at least 20 Kcal/Mol are applied to the gauge.

7. A gauge set according to claim 1, comprising at least 10,000 distinct gauges.

8. A gauge set according to claim 1, comprising at least 50,000 distinct gauges.

9. A gauge set according to claim 3, wherein at least 50% of said gauges are defined by adding moieties to a set of fewer than 100 scaffolds.

10. A gauge set according to claim 3, wherein at least 50% of said gauges are defined by adding moieties to a set of fewer than 50 scaffolds.

11. A gauge set according to claim 1, using fewer than 15 different chemical moieties to define the chemical behavior of said gauges.

12. A gauge set according to claim 1, using fewer than 10 different chemical moieties to define the chemical behavior of said gauges.

13. A gauge set according to claim 1, wherein said gauges comprise moieties selected from the group consisting of hydroxyl (OH), carboxyl (COOH), amide (CONH₂), ethyl (CH₂—

CH₃), propyl (CH₂—

CH₂—

CH₃), and phenyl.

14. A gauge set according to claim 3, wherein said rigid scaffold comprises one or more rings.

15. A gauge set according to claim 14, wherein all single bonds in said scaffold are part of a ring or attach an atom to a ring.

16. A gauge set according to claim 14, wherein said rings do not include a ring comprising more than 6 atoms and more than two adjacent single bonds, wherein the atoms of said adjacent single bonds participate only in single bonds.

17. A gauge set according to claim 14, comprising gauges defined by adding moieties to a set of at least 4 scaffolds that have exactly three rings.

18. A gauge set according to claim 14, comprising gauges defined by adding moieties to a set of at least 4 scaffolds that have exactly four rings. 163

19. A gauge set according to claim 1, wherein for a portion of said triangle space which defines all possible 3-point pharmacophores defined by a triplet of distances that form a triangle, each distance being in a range of 4-12 angstrom:

for each point in 50% of said portion of triangle space, said set of gauges comprises at least six gauges with a substantially rigid triangular configuration of binding points capable of chemically binding to a 3-point pharmacophore corresponding to said point.

20. A method of obtaining information about a chemically active area of a target molecule, comprising:

providing the gauge set of claim 1;

causing said target to interact with a plurality of gauges of said set of gauges;

assaying said interaction of said gauges with said target to obtain a plurality of assay results; and

analyzing said assay results to obtain information about said chemically active area.