Replica exchange molecular dynamics toolkit for drug--receptor docking

M. Ito , T. Nishikawa and U. Nagashima
National Institute of Advanced Industrial Science and Technology, JP

Keywords: replica, exchange, MD, drug, discovery, receptor, docking, simulation

Abstract:
In this post-genomic era, much attention is focused on the 3D structure and flexibility of protein molecules for the rational drug design. Although the structure information provides a good starting point for estimating the ligand-protein binding affinity, the treatment of protein structural fluctuations remains a major challenge to docking simulation programs. To deal with this problem, we have developed a new software toolkit with enhanced efficiency of conformational sampling by replica exchange molecular dynamics (REMD) method. Our toolkit is designed for docking simulation, structure refinement, and free energy calculation, and is being integrated into the rational drug design system. In the system, a set of ligand molecules is filtered first by ligand conformational analysis, and the resultant candidates will be further screened by our REMD simulation with the estimate of the relative binding free energy which is also utilized for other analysis such as quantitative structure--activity relationship (QSAR). As a critical test of our toolkit, we are applying it to the prediction of the binding affinity of several HIV protease inhibitors.

NSTI Nanotech 2003 Conference Technical Program Abstract