Methods for rapidly indentifying small organic molecule ligands for binding to biological target molecules
First Claim
5. The method according to claim 1, wherein said biological target molecule comprises said chemically reactive group without prior modification of said target molecule.
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Abstract
The present invention is directed to novel methods for rapidly and unambiguously identifying small organic molecule ligands for binding to biological target molecules. Small organic molecule ligands identified according to the methods of the present invention may find use, for example, as novel therapeutic drug lead compounds, enzyme inhibitors, labeling compounds, diagnostic reagents, affinity reagents for protein purification, and the like. Also presented are novel methods for identifying high affinity binding ligands for a biological target molecule of interest, wherein those methods comprise linking two or more small organic molecule ligands previously identified as being capable of binding to the biological target molecule of interest. Biological target molecules include, for example, polypeptides, nucleic acids, carbohydrates, nucleoproteins, glycoproteins, glycolipids and lipoproteins.
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Citations
39 Claims
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5. The method according to claim 1, wherein said biological target molecule comprises said chemically reactive group without prior modification of said target molecule.
- 6. The method according to claim 1, wherein said biological target molecule obtained in step (a) has been modified to comprise said chemically reactive group.
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8. The method according to claim 1, wherein said library of organic compounds comprises aldehydes, ketones, oximes, hydrazones, semicarbazones, carbazides, primary amines, secondary amines, tertiary amines, N-substituted hydrazines, hydrazides, alcohols, ethers, thiols, thioethers, thioesters, disulfides, carboxylic acids, esters, amides, ureas, carbamates, carbonates, ketals, thioketals, acetals, thioacetals, aryl halides, aryl sulfonates, alkyl halides, alkyl sulfonates, aromatic compounds, heterocyclic compounds, anilines, alkenes, alkynes, diols, amino alcohols, oxazolidines, oxazolines, thiazolidines, thiazolines, enamines, sulfonamides, epoxides, aziridines, isocyanates, sulfonyl chlorides, diazo compounds and acid chlorides.
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9. The method according to claim 1, wherein said library of organic compounds comprises primary amines, secondary amines, aldehydes or ketones.
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10. The method according to claim 1, wherein said chemically reactive group is a primary amine group, a secondary amine group, an aldehyde group or a ketone group.
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11. The method according to claim 1, wherein step (c) is accomplished by a process that employs mass spectrometry.
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12. The method according to claim 1, wherein step (c) comprises fragmenting said target molecule/organic compound conjugate into two or more fragments.
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13. The method according to claim 1, wherein subsequent to step (b) and prior to step (c) said target molecule/organic compound conjugate is combined with one or more members of a library of organic molecules that are capable of covalently bonding to the organic compound previously bound to said target molecule, wherein at least one member of said library of organic molecules binds to said target molecule/organic compound conjugate.
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14. A method for identifying an organic molecule ligand that binds to a biological target molecule of interest, said method comprising:
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(a) obtaining a biological target molecule that comprises or has been modified to comprise a first reactive functionality, (b) reacting said target molecule with a compound that comprises (1) a second reactive functionality and (2) a chemically reactive group, wherein said second reactive functionality reacts with said first reactive functionality of said target molecule to form a covalent bond, thereby resulting in said chemically reactive group being linked to said target molecule through a covalent bond;
(c) combining said target molecule with one or more members of a library of organic compounds that are capable of covalently bonding to said chemically reactive group, wherein at least one member of said library forms a covalent bond with said chemically reactive group to form a target molecule/organic compound conjugate; and
(d) identifying the organic compound that forms a covalent bond with said chemically reactive group. - View Dependent Claims (15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)
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32. A method for identifying a ligand that binds to a biological target molecule of interest, said method comprising:
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(a) identifying a first organic molecule ligand that binds to said biological target molecule by the method of claim 1;
(b) identifying a second organic molecule ligand that binds to said biological target molecule by the method of claim 1; and
(c) linking said first and second organic molecule ligands through a linker element to form a conjugate molecule that binds to said biological target molecule. - View Dependent Claims (33, 34, 35, 36, 37, 38, 39)
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Specification