KNOBLE: A Knowledge-Based Approach for the Design and Synthesis of Readily Accessible Small-Molecule Chemical Probes To Test Protein Binding

摘要

At the beginning of the last decade, potent high-throughput technologies stimulated the development of combinatorial chemistry as a productive source of candidate molecules suited for screening biological activity against putative drug targets. However, the sheer increase of readily available test compounds has not dramatically enhanced the efficiency of lead discovery. As a consequence, compound selection for testing is moving increasingly from "optimally diverse" sets to targeted compound libraries. As proteins occur in families characterized by conserved binding motifs, they can be addressed by ligand skeletons exhibiting binding epitopes complementary to the commonly exposed properties of the protein family. Accordingly, efficient design of targeted compound libraries starts with a central privileged skeleton that specifically addresses the exposed binding motif of a protein family.