(567a) Elucidating Molecular Origins of Drug Selectivity for Rational Design of Selective Drugs

Proteins families that evolve to bind particular ligand also contain diverse members that exhibit a wide range of affinities for that particular ligand. However, this variance in affinity resulting from evolution of the family members is usually at odds with the high sequence and structure similarity shared by its members. In this talk, we discuss three such protein families i.e. human protein kinases, Cannabinoid receptors and Strigolactone receptors in plants. These proteins show several orders of magnitude difference in their ligand affinity but share high sequence and structural similarity. The characterization of the free energy landscapes for ligand binding starting could shed light on the molecular origin of their ligand selectivity mechanisms. In order to achieve this goal, we have develop computational methods for evaluation of their binding mechanism using molecular simulations. These examples served as model system for obtaining generalizable insights about the free energy landscapes of ligand binding that could help design of drugs with desired selectivity profiles.