Abstract

Fragment-Based Drug Discovery Based on Diversity-Oriented Synthesis

Damian Young, Assistant Director, Center for Drug Discovery, Baylor College of Medicine

Diversity-oriented synthesis (DOS) is a conceptual approach aimed at guiding the synthesis of small-molecule collections having disparate structural features for screening. Fragment based drug discovery (FBDD) involves the screening of low molecular weight (<300 MW) ligands against defined protein targets using biophysical binding assays. Research in the Young laboratory has centered on combining the two strategies toward a more effective and efficient means of generating therapeutic leads against challenging disease targets. Using the principles of DOS, compounds possessing diverse 3-dimensional structures have been synthesized while maintaining the molecular weight under 300MW. This diverse fragment collection will have greater discovery potential toward a variety of distinct biomolecular targets given their greater structural diversity.Moreover, because DOS syntheses rely on highly modular routes, the optimization of fragment hits is achieved with high precision and efficiency. Examples involving the application of DOS to FBDD against specific cancer targets will be presented.