Methods for identifying drug cores
OwnerJonathan Moore, Guy William Bemis +5inventors
InventorsJonathan Moore, Guy William Bemis, Christopher A. Lepre, Jasna Fejzo, Jeffrey Weilee Peng, Keith Phillip Wilson, Mark Andrew Murcko
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Abstract
The present invention relates to methods for detecting chemical moieties that may serve as the core or scaffold of a potential drug that is directed to a target. The invention further relates to a chemical library of drug cores and the use of that library to identify useful drug cores for a particular target protein.
Claims14
A method of identifying a drug core suitable for a given target comprising the steps of:
- a. providing a drug core consisting of a cyclic structure or a tautomer thereof selected from:
- 22 23
- wherein said cyclic structure is optionally substituted at:
- i) one or more carbon atoms with one or more substituents independently selected from ═O, —CH3, —OH, —OCH3, —Cl, —NH2, —C(O)OH, —F, —CH2OH, —CH2CH3, —OC(O)CH3, —NO2, —N(CH3)2, —CF3, —C(O)NH2, —C(O)OCH3, —C(O)OCH2CH3, —CH(CH3)2, —S(O)2NH2, —C(O)CH3, —CN, —Br, —I, —S(O)2OH, —OCH2CH31—CH2C(O)OH, —OC(O)CH2CH3, —CH2CH(CH3)2, —C(O)CH2OH, —NH—C(O)CH3, —C(CH3)3, ═S, —CH2NH2, —OCH2CHOHCH2NHC(CH3)3, —NHCH3, —C(CH3)C(O)OH, —C=—CH, —(CH2)2CH3, —CH2C(O)NH2, —OCH2CHOHCH2NHCH(CH3)2, ═N—OCH3, or —OCH2CH3
- ii) one or more nitrogen atoms, if present, with a substituent independently selected from —CH3, —(CH2)2OH or —CH2CH3;
- and
- iii) a sulfur atom, if present, with ═O;
- and
- c) determining whether any one of said drug cores binds to said target.
A method of calculating the dissociation constant, Kd, between a ligand and a target comprising the steps of:
- a) obtaining a one-dimensional NMR spectra of said ligand in the absence of said target at various gradient strengths;
- b) mixing the target with the ligand at a molar ratio of between 1:1 and 1:20.
- c) subjecting said mixture to nuclear magnetic resonance for a period of time sufficient to obtain one-dimensional spectra at the same gradient strengths utilized in step i;
- and
- d) utilizing the spectral data generated in steps i) and iii) to calculate the Kd between said ligand and said target.
A plurality of individually compartmentalized compounds consisting of:
- a) at least one compound of the formula:
- 26
- b) at least one compound of the formula:
- 27
- c) at least one compound of the formula:
- 28
- d) at least one compound of the formula:
- 29
- e) at least one compound of the formula:
- 30
- f) at least one compound of the formula:
- 31
- g) at least one compound of the formula:
- 32
- h) at least one compound of the formula:
- 33
- i) at least one compound of the formula:
- 34
- j) at least one compound of the formula:
- 35
- k) at least one compound of the formula:
- 36
- l) at least one compound of the formula:
- 37
- n) at least one compound of the formula:
- 38
- and tautomers thereof;
- and optionally includes any of:
- 39
- wherein:
- V is N or O;
- W is N or S;
- X is C or N;
- Y is C, N or 0;
- Z is selected from a bond, —CH2—, —NH—, —O— or —N—CH2
- R2 is a 6-membered carbocyclic ring containing 1, 2 or 3 double bonds
- R3, if present, is methylenedioxy;
- and wherein
- any of said compounds is optionally substituted on one or more carbon atoms with one or more substituents independently selected from ═O, —OH, halo, —CN, —(C1-C3)-straight or branched alkyl, —N(R4)2, —C(O)—R5, —OR6, —CH2H, —CF3, —S(O)2NH2;
- any of said compounds is optionally substituted on one or more nitrogen atoms, if present, with a —(C1-C3)-straight or branched alkyl;
- and
- any of said compounds is optionally substituted on a sulfur atom, if present, with ═O;
- wherein each R4 is independently selected from H, O, or —(C1-C3)-straight or branched alkyl;
- each R5 is selected from OH, O—(C1-C3)-straight or branched alkyl, NH2, or (C1-C3)-straight or branched alkyl;
- and
- each R6 is selected from —(C1-C3)-straight or branched alkyl, or C(O)—(C1-C3)-straight or branched alkyl.
Dependencies are inferred from the claim text.