Methods for rapidly identifying small organic molecule ligands for binding to biological target molecules
First Claim
1. A process comprising(a) screening a library of small organic compounds, less than about 2000 daltons in size, with a target protein-ligand conjugate formed by the covalent bonding of a target protein comprising a first reactive functionality with a ligand that (1) comprises less than about 20 carbon atoms;
- (2) has affinity for interacting with a particular site on the target protein, (3) comprises a second reactive functionality and (4) comprises a free chemically reactive group, wherein the second reactive functionality of the ligand reacts with the first reactive functionality of the target protein to form a first covalent bond such that the ligand in the target protein-ligand conjugate contains a free chemically reactive group, in aqueous solution, under conditions wherein at least one member of the library forms a second covalent bond with said free chemically reactive group in the target protein-ligand conjugate, and (b) determining the identity of a small organic compound that binds covalently to the free chemically reactive group of the target protein-ligand conjugate.
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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
16 Claims
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1. A process comprising
(a) screening a library of small organic compounds, less than about 2000 daltons in size, with a target protein-ligand conjugate formed by the covalent bonding of a target protein comprising a first reactive functionality with a ligand that (1) comprises less than about 20 carbon atoms; - (2) has affinity for interacting with a particular site on the target protein, (3) comprises a second reactive functionality and (4) comprises a free chemically reactive group, wherein the second reactive functionality of the ligand reacts with the first reactive functionality of the target protein to form a first covalent bond such that the ligand in the target protein-ligand conjugate contains a free chemically reactive group, in aqueous solution, under conditions wherein at least one member of the library forms a second covalent bond with said free chemically reactive group in the target protein-ligand conjugate, and
(b) determining the identity of a small organic compound that binds covalently to the free chemically reactive group of the target protein-ligand conjugate. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
- (2) has affinity for interacting with a particular site on the target protein, (3) comprises a second reactive functionality and (4) comprises a free chemically reactive group, wherein the second reactive functionality of the ligand reacts with the first reactive functionality of the target protein to form a first covalent bond such that the ligand in the target protein-ligand conjugate contains a free chemically reactive group, in aqueous solution, under conditions wherein at least one member of the library forms a second covalent bond with said free chemically reactive group in the target protein-ligand conjugate, and
Specification