Receptor conformational sampling through normal mode analysis and its application to virtual screening

KOVACS, JULIO A.; CAVASOTTO, CLAUDIO N.; ABAGYAN, RUBEN A.

Long Beach, CA

Conferencia; 49th Annual Meeting of the Biopysical-Society; 2005

The consideration of protein flexibility in structure-based drug design is a real challenge for modern computational biology. The best currently available approach to incorporate protein fluctuations in ligand docking and scoring is the use of multiple receptor backbone conformations. We present a method based on normal mode analysis performed in internal coordinates to generate an ensemble of structurally diverse protein conformations. The ensemble structures are then complexed with known binders spanning different chemotypes, and the energy of the system is minimized using a stochastic global energy optimization algorithm. After re-evaluating the energy by including terms for entropy and solvation, the receptor conformation corresponding to the lowest energy complex for each ligand is selected to perform a small-scale virtual screening. It is found that the ensemble of structures thus generated represents the conformational space of the receptor, and reported enrichment factors are better than those considering a single-structure screening. Thus, this method represents a valid approach to incorporate protein backbone flexibility in ligand docking and screening.