COMPOUNDS AND METHODS FOR THE TREATMENT OF VIRAL INFECTIONS
First Claim
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1. A virtual screening method of identifying anti-viral compounds that bind to a nucleoprotein binding site comprising:
- a) obtaining the structural coordinates of a nucleoprotein;
b) applying 3-dimensional molecular modeling to the structural coordinates of the nucleoprotein binding pocket; and
c) screening spatial coordinates of the compound against the spatial coordinates of the nucleoprotein binding pocket to determine if the compound binds within the nucleoprotein binding pocket.
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Abstract
High throughput and virtual screening methods are disclosed that can identify potential anti-viral agents. The virtual screening methods identify agents that interact with a viral nucleoprotein binding site. The high throughput methods identify compounds that inhibit viral infection by binding to viral nucleoprotein. Also disclosed are pharmaceutical formulations useful for treating or preventing viral infections, especially influenza A.
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Citations
42 Claims
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1. A virtual screening method of identifying anti-viral compounds that bind to a nucleoprotein binding site comprising:
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a) obtaining the structural coordinates of a nucleoprotein; b) applying 3-dimensional molecular modeling to the structural coordinates of the nucleoprotein binding pocket; and c) screening spatial coordinates of the compound against the spatial coordinates of the nucleoprotein binding pocket to determine if the compound binds within the nucleoprotein binding pocket. - View Dependent Claims (3, 5, 7)
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2. A virtual screening method for identifying anti-viral compounds that bind to influenza A NP nucleozin binding site comprising:
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a) obtaining the structural coordinates of an influenza A NP; b) applying three-dimensional molecular modeling to the structural coordinates of an influenza A NP binding pocket defined by the structural coordinates of at least amino acid residues 280 to 311; and c.) screening spatial coordinates of the compound against the spatial coordinates of the influenza A NP binding pocket to determine if the compound binds within the influenza A NP binding pocket. - View Dependent Claims (4, 6, 8)
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9. An antiviral compound having one of the following chemical formulae:
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Ar1—
Y—
Ar2—
X-Cy-Z—
Ar3
(formula I)wherein Ar1, Ar2, and Ar3 are each independently substituted or unsubstituted aryl or heteroaryl groups; X, Y, and Z are independently absent (i.e, a direct bond) or selected from —
C(═
O)—
, —
S(═
O)—
, —
SO2—
, —
C(═
O)N(R1), —
N(R2)—
, —
C(R3)═
C(R4)—
, and —
C(R5R6)n—
;n is 0 to 10; R1-R6 are each independently selected from hydrogen;
halogen;
hydroxy;nitro;
nitrile;
isonitrile;
urea;
guanidine;
cyano;
formyl, acyl, carboxyl;
thioester, thioacetate, thioformate;
primary, secondary, or tertiary amine;
amide;
amidine;
imine;
azide;
thiol, substituted or unsubstituted thioalkyl;
isocyanate;
isothiocyanate;
phosphoryl;
phosphate;
phosphinate;
sulfate;
sulfonate;
sulfamoyl;
sulfonamide;
sulfonyl;
substituted or unsubstituted linear or branched alkyl, alkenyl, or alkynyl;
substituted or unsubstituted linear or branched alkoxy;
substituted or unsubstituted C3-C10 cycloalkyl, cycloalkenyl, heterocyloalkyl, or heterocycloalkenyl;
substituted or unsubstituted aryl or heteroaryl; andCy is a 5-7 membered substituted or unsubstituted cyclic or heterocyclic group; - View Dependent Claims (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 38, 39, 40, 41, 42)
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37. A compound with the following structure:
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[4-(2-chloro-4-nitro-phenyl)-piperazin-1-yl]-[3-(4-hydroxy-phenyl)-5-methylisoxazol-4-yl]-methanone; [4-(2-chloro-4-nitro-phenyl)-piperazin-1-yl]-[3-phenyl-5-methyl-isoxazol-4-yl]-methanone; [4-(2-chloro-4-nitro-phenyl)-piperazin-1-yl]-[3-(4-amino-phenyl)-methylisoxazol-4-yl]-methanone; [4-(2-chloro-4-nitro-phenyl)-piperazin-1-yl]-[3-(4-azido-phenyl)-5-methylisoxazol-4-yl]-methanone; [4-(2-chloro-4-nitro-phenyl)-piperazin-1-yl]-[3-(2-chloro-phenyl)-5-methylisoxazol-4-yl]-methanone; [4-(2-chloro-4-nitro-phenyl)-2-methyl-piperain-1-yl]-[3-(2-chloro-phenyl)-5-methyl-isoxazol-4-yl]-methanone; [4-(2-chloro-4-nitro-phenyl)-2-methyl-piperain-1-yl]-[3-phenyl-5-methylisoxazol-4-yl]-methanone; [4-(4-nitro-phenyl)-piperazin-1-yl]-[3-(2-chloro-phenyl)-5-methyl-isoxazol-4-yl]-methanone; and [4-(4-nitro-phenyl)-piperazin-1-yl]-[3-(2,6-dichloro-phenyl)-5-methyl-isoxazol-4-yl]-methanone.
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Specification