Methods for rapidly identifying small organic molecule ligands for binding to biological target molecules

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.

Description

FIELD OF THE INVENTION[0001]The present invention is directed to novel molecular methods useful for quickly and unambiguously identifying small organic molecule ligands for binding to specific sites on target biological molecules. Small organic molecule ligands identified according to the methods of the present invention find use, for example, as novel therapeutic drug lead compounds, enzyme inhibitors, labeling compounds, diagnostic reagents, affinity reagents for protein purification, and the like.BACKGROUND OF THE INVENTION[0002]The primary task in the initial phase of generating novel biological effector molecules is to identify and characterize one or more tightly binding ligand(s) for a given biological target molecule. In this regard, many molecular techniques have been developed and are currently being employed for identifying novel ligands that bind to specific sites on biomolecular targets, such as proteins, nucleic acids, carbohydrates, nucleoproteins, glycoproteins and g...

AI Technical Summary

Benefits of technology

[0007]Applicants herein describe a molecular approach for rapidly and efficiently identifying small organic molecule ligands that are capable of interacting with and binding to specific sites on biological target molecules, wherein ligand compounds identified by the subject methods may find use, for example, as new small molecule drug leads, enzyme inhibitors, labeling compounds, diagnostic reagents, affinity reagents for protein purification, and the like. The herein described approaches allow one to quickly screen a library of small organic compounds to unambiguously identify those that have affinity for a particular site on a biomolecular target. Those exhibiting affinity for interacting with a particular site are capable of forming a covalent bond with a chemically reactive group at that site, whereby small organic compounds capable of covalent bond formation may be readily identified and characterized. Such methods may be performed quickly, easily and inexpensively and provide for unambiguous results. The small organic molecule ligands identified by the methods described herein may themselves be employed for numerous applications, or may be coupled together in a variety of different combinations using one or more linker elements to provide novel binding molecules.

Problems solved by technology

While combinatorial approaches for identifying biological effector molecules have proven useful in certain applications, these approaches also have some significant disadvantages.

For example, current synthetic technology is limited in that it allows one to synthesize only a relatively small fraction of the total number of possible library members for any given molecule type.

Thus, combinatorial approaches often do not allow one to identify the “best” ligand for a target molecule of interest.

Additionally, even when appropriate screening assays are available, in many cases techniques which allow identification of the actual library member(s) which bind most effectively to the target are not available or provide ambiguous results, making the actual identification and characterization of functional ligand molecules difficult or impossible.

Furthermore, many approaches currently employed to identify novel ligands are dependent upon only a single specific chemistry, thereby limiting the usefulness of such approaches to only a narrow range of applications.

Finally, many of the approaches currently employed are expensive and extremely time-consuming.