Drug discovery method

• US 20050277117A1
• Filed: 07/24/2002
• Published: 12/15/2005
• 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 8,019,550 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• 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 method of obtaining information about a chemically active area of a target molecule, comprising:

providing a set of substantially rigid chemical gauges;

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.

2. A method according to claim 1, wherein said gauges allow rotation of moieties of said gauges.

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

4. A method 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.

5. A method according to claim 1, wherein analyzing comprises identifying a plurality of spatial and chemically specific bindings configurations in said target active area.

6. A method according to claim 5, wherein said configurations comprise triangular configurations.

7. A method according to claim 5, wherein identifying comprises identifying a configuration that matches a configuration of a bound gauge.

8. A method according to claim 5, wherein identifying comprises identifying a configuration that does not match a configuration of a bound gauge.

9. A method according to claim 8, wherein identifying comprises identifying by statistical analysis of said assay results.

10. A method according to claim 9, wherein identify comprises identifying by clustering.

11. A method according to claim 5, wherein identifying comprises assuming each gauge indicates a single configuration.

12. A method according to claim 5, wherein identifying comprises assuming at least some of the gauges indicate a plurality of configurations.

13. A method according to claim 5, wherein identifying comprises classifying gauges by chemical moieties at vertexes of said configurations.

14. A method according to claim 1, comprising reconstructing a spatial map of at least part of said chemically active area, from at least two of said assay results, said part including at least four chemical binding areas.

15. A method according to claim 14, wherein said part includes at least six chemical binding areas.

16. A method according to claim 5, comprising reconstructing a spatial map of at least part of said chemically active area, from at least two of configurations, said part including at least four chemical binding points.

17. A method according to claim 16, wherein said part includes at least six chemical binding areas.

18. A method according to claim 16, wherein reconstructing comprises:

test-reconstructing a plurality of spatial maps from said configurations;

scoring said maps; and

selected a spatial map based on its score.

19. A method according to claim 16, wherein reconstructing comprises:

test-reconstructing a plurality of spatial maps from said configurations;

clustering said maps according to common substructures; and

selected a spatial map based on a relative property of a cluster it belongs to.

20. A method according to claim 19, wherein said relative property comprises size.

21. A method according to claim 16, wherein said spatial map includes enough binding points to ensure binding of a small molecule drug having a chemical profile matching the binding points.

22. A method according to claim 21, wherein said spatial map includes at least 6 binding points.

23. A method according to claim 21, wherein said spatial map includes at least 8 binding points.

24. A method according to claim 1, wherein said set of gauges comprises a set of gauges with at least 10,000 gauges.

25. A method according to claim 1, wherein said set of gauges comprises a set of gauges with at least 50,000 gauges.

26. A method according to claim 1, wherein said gauges comprise moieties arranged in spatial configurations and wherein said gauges are selected to span a virtual space of spatial chemical configurations.

27. A method according to claim 1, wherein substantially each point of virtual space that is spanned by said gauges is covered by at least two gauges.

28. A method according to claim 1, wherein substantially each point of virtual space that is spanned by said gauges is covered by at least three gauges.

29. A method according to claim 1, wherein at least 0.5% of said gauges bind with said target.

30. A method according to claim 1, wherein at least 1% of said gauges bind with said target.

31. A method according to claim 1, wherein at least 3% of said gauges bind with said target.

32. A method according to claim 1, wherein at least 50% of said gauges are defined by adding moieties to a set of fewer than 100 scaffolds.

33. A method according to claim 1, wherein at least 50% of said gauges are defined by adding moieties to a set of Fewer than 50 scaffolds.

34. A method according to claim 1, wherein at least said set of gauges uses fewer than 15 different chemical moieties to define the chemical behavior of said gauges.

35. A method according to claim 1, wherein at least said set of gauges uses fewer than 10 different chemical moieties to define the chemical behavior of said gauges.

36. A method according to claim 1, wherein said assay is a functional assay.

37. A method according to claim 1, wherein said assay is a binding assay.

38. A method according to claim 1, wherein said assay is a cellular assay.

39. A method according to claim 1, wherein said assay is a flow-through assay.

40. A method according to claim 36, wherein said functional assay is performed in the presence of a natural substrate of said target.

41. A method according to claim 1, wherein said target comprises a protein including a biochemically active area adapted to engage a substrate.

42. A method according to claim 41, wherein said chemically active area comprises an area including said biochemically active area.

43. A method according to claim 41, wherein said chemically active area comprises a control area of said protein.

44. A method according to claim 1, analyzing comprises analyzing successful binding of at least 60 gauges.

45. A method according to claim 1, analyzing comprises analyzing successful binding of at least 10 gauges.

46. A method according to claim 1, analyzing comprises analyzing successful binding of at least 100 gauges.

47. A method according to claim 5, wherein identifying comprises identifying at least 40 different configurations.

48. A method according to claim 5, wherein identifying comprises identifying at least 10 different configurations.

49. A method according to claim 5, wherein identifying comprises identifying at least 100 different configurations.

50. A method according to claim 16, comprising:

comparing said map to a lead data base; and

selecting a lead from said data base for further use responsive to a semblance or lack of semblance between said lead and said map.

51. A method according to claim 16, comprising:

comparing said map to a lead data base; and

rejecting a lead from said data base for further use responsive to a semblance between said lead and said map.

52. A method according to claim 16, comprising:

constructing a lead to have a semblance to said map.

53. A method according to claim 52, wherein constructing comprises constructing using said gauges or scaffolds used to define said gauges.

54. A method according to claim 5, comprising:

comparing said configurations to a lead data base; and

selecting a lead from said data base for farther use responsive to a matching of said configurations to said lead.

55. A method according to claim 5, comprising:

constructing a lead based on said configurations.

56. A method according to claim 5, comprising:

selecting at least one of said gauges as a lead for drug discovery.

57. A method according to claim 1, comprising comparing the binding of gauges with similar binding geometries to obtain steric clashing data;

and

analyzing said steric clashing data to provide geometrical information about said target.

102. A method according to claim 1, comprising generating a set of drug leads for said target based on said information.

103. A method according to claim 102, comprising removing known drug leads for said target from said set

155. A method according to claim 1, wherein said analyzing comprises characterizing said chemically active area.

156. A method according to claim 155, wherein said chemically active area comprises at least two disjoint chemically active areas.

157. A method according to claim 1, wherein said analyzing comprises taking said rigidity into account of said analyzing.

158. A method according to claim 1, wherein said target molecule comprises an agricultural chemical target.

159. A method according to claim 1, wherein said target molecule comprise a drug target.

160. A method according to claim 1, wherein, on the averages each point of virtual space that is spanned by said gauges is covered by between 1.1 and 2 gauges.

161. A method according to claim 1, wherein at least 0.1% of said gauges bind with said target.

162. A method according to claim 1, wherein the moieties comprise Hydroxyl (OH), Carboxyl (COOH), Amide (CONH2). Ethyl (CH2-CH3), Propyl (CH2-CH2-CH3), Phenyl (C6H5, 6 member aromatic ring).

163. A method according to claim 1, wherein said chemically active area comprises at least two disjoint chemically active areas.

58-101. -101. (canceled)

104-154. -154. (canceled)

164. A method of mapping an active area of a biological target, comprising:

providing a set of chemical gauge molecules, each gauge molecule having a geometric structure;

assaying an interaction between a plurality of said chemical gauge molecules and the biological target; and

mapping the active area according to the results of assaying said interactions and according to said gauge molecule geometric structures.

165. A method according to claim 164, wherein said gauge molecules are rigid molecules.

166. A method according to claim 164, in which the gauge molecules are composed of a rigid scaffold and to which various chemical moieties are attached using one rotationally free bond.

167. A method according to claim 166, wherein the rigid scaffold containing no rotationally free bonds