FASTDock: A Pipeline for Allosteric Drug Discovery.

ABSTRACT

Allostery is involved in innumerable biological processes and plays a fundamental role in human disease. Thus, the exploration of allosteric modulation is crucial for research on biological mechanisms and in the development of novel therapeutics. The development of small-molecule allosteric effectors can be used as tools to probe biological mechanisms of interest. One of the main limitations in targeting allosteric sites is the difficulty in uncovering them for specific receptors. Furthermore, upon discovery of novel allosteric modulation, early lead generation is made more difficult as compared to that at orthosteric sites because there is likely no information about the types of molecules that can bind at the site. In the work described here, we present a novel drug discovery pipeline, FASTDock, which allows one to uncover ligandable sites as well as small molecules that target the given site without requiring pre-existing knowledge of ligands that can bind in the targeted site. By using a hierarchical screening strategy, this method has the potential to enable high-throughput screens of an exceptionally large database of targeted ligand space.