Alladi Ramakrishnan Hall

Computational Methods for Structure Based Drug Design

E. Prabhu Raman

Computer Aided Drug Design Center Univ. of Maryland School of Pharmacy

Structure based drug design (SBDD) aims to discover small
molecules that can bind with high affinity to a receptor of known 3D
structure. Fragment based drug design (FBDD), a sub-class of SBDD
methods, involves finding small molecular fragment binders, rather
than large typical drug-sized molecules. The talk will be divided into
two parts. Part I will describe the development and application of a
computational method for SBDD that maps the protein affinity pattern
for various chemical functionalities by performing MD simulations
(called SILCS) in a solution of fragments. I will talk about my
efforts to rank-order ligands by affinity, based on the information
obtained from SILCS simulations. Next, I will describe a method for
extrapolating the affinities of multiple similar fragments from the
explicit MD sampling of a single fragment. The application of these
methods in the fragment-based de-novo discovery of a protein-protein
interaction inhibitor will be described. Part II will start by a
description of the state-of-the-art in computational methods for SBDD,
which will also highlight the limitations in the present
methodologies. I will then describe a method that I developed recently
for the rapid calculation of water-binding free energies to protein
pockets. The talk will conclude with a discussion of future directions
of this method for receptor-ligand free energy calculations.