Drug discovery method

• US 9,405,885 B2
• Filed: 06/06/2011
• Issued: 08/02/2016
• Est. Priority Date: 07/24/2002
• Status: Expired due to Term

• Current Assignee: Keddem Bioscience Ltd. (Compugen Ltd)
• Original Assignee: Keddem Bioscience Ltd. (Compugen Ltd)
• Inventors: Ofer, Dror
• Primary Examiner(s): Flinders, Jeremy C
• Application Number:
  US13/153,487
• Publication Number:
  US 20110237458A1
• Time in Patent Office: 1,884 Days
• US Class Current: 1/1
• 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 gauge molecules;

causing said target to singly interact with each of a plurality of gauges of said set of gauges, said plurality comprising at least 5,000 gauges;

assaying said interaction of said gauges with said target to assay binding of said gauges to said target, so as to obtain at least 5 gauges which bind to said target; and

analyzing a structure of said target bound to each of said at least 5 gauges; and

finding a set of binding points in said target which bind to the same chemical type of moiety in at least two of said at least 5 gauges; and

identifying binding points in set said of binding points in said target as binding points which bind to the same chemical type of moiety in at least two of said at least 5 gauges; and

reconstructing a spatial map of identified binding points, said spatial map comprising at least 4 identified binding points in said target, each of said identified binding points being identified as binding to the same chemical type of moiety in at least two of said gauges,

to thereby obtain information about said chemically active area,

wherein said plurality of gauges is selected so as to comprise triangles of moieties capable of binding to the 3-point pharmacophores in at least 40% of 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.

2. The method of claim 1, wherein said analyzing comprises analyzing using a technique selected from the group consisting of NMR and X-ray crystallography.

3. The method of claim 1, wherein at least 60% of gauges of said plurality of gauges are substantially rigid.

4. The method of claim 1, comprising obtaining at least 25 gauges which bind to said target, and analyzing a structure of said target bound to each of said at least 25 gauges.

5. The method of claim 1, comprising virtually super-imposing a plurality of structures obtained by said analyzing.

6. The method of claim 5, wherein said super-imposing uses said target as a reference frame.

7. The method of claim 1, wherein said identifying comprises identifying at least one 3-point pharmacophore in said target which bind to a triangular configuration of moieties in at least two of said at least 5 gauges.

8. The method of claim 1, wherein said plurality of gauges spans at least 40% of said triangle space with an overlap of 3.

9. The method of claim 1, wherein said binding points in said target bind to a compatible type of moiety of said at least two of said at least 5 gauges.

10. The method of claim 1, wherein said binding points in said target and said moieties of said gauges are characterized by a chemical type selected from the group consisting of acid, base, hydrophobic, hydrogen bond donor, hydrogen bond acceptor and aromatic.

11. The method of claim 1, wherein said finding a set of binding points comprises finding a set of binding points in said target which bind to the same type of moiety in at least three of said at least 5 gauges.

12. The method of claim 1, wherein said plurality of gauges comprises at least 10,000 gauges.

13. The method of claim 1, wherein said at least 5 gauges bind to said target at a concentration of 100 μ

M.

14. The method of claim 1, wherein said spatial map comprises at least 6 binding points of said target, each of said at least 6 binding points being identified as binding to the same chemical type of moiety in at least two of said at least 5 gauges.

15. The method of claim 14, further comprising selecting and/or constructing a drug candidate to match said spatial map identified binding points.

16. The method of claim 1, wherein said plurality of gauges comprises 3-methyl-5-phenyl-anthranilic acid.

17. The method of claim 1, comprising using a same set of gauge molecules for obtaining information about a different target molecule.

18. The method of claim 1, wherein said finding comprises identifying a set of three binding moieties and distances between the moieties.

19. The method of claim 1, wherein said assaying is at between 1 and 100 micro Molar.

20. The method of claim 1, wherein said reconstructing comprises reconstructing based on most of the successful binding assays.

21. The method of claim 14, wherein said spatial map comprises 10 binding points.

22. The method of claim 1, wherein said binding points of said spatial map comprise generic binding points with sufficient chemical freedom for a range of binding molecules.

23. The method of claim 1, wherein said binding points of said spatial map include at least one donor/acceptor binding point which is unidentified as a donor or acceptor.

24. The method of claim 1, wherein said binding points of said spatial map include at least one binding point allowing a variety of directional bindings thereto.

25. The method of claim 1, wherein said set of gauges is selected to cover a range of bond direction for a directional same bond, so as to be usable in a range of target molecules.

26. the method of claim 25, wherein said range is uniform.

27. The method of claim 1, wherein said set of gauges is selected so that said binding point types are generic for a range of target molecules.

28. The method of claim 1, wherein, at least 20% of gauges of said plurality of gauges are substantially rigid.