Incorporating receptor flexibility in ligand docking and virtual screening through a normal made analysis-based procedure

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

Bethesda, MD

Conferencia; 48th Annual Meeting of the Biophysical Society; 2004

Virtual screening of chemical libraries is expected to play an increasing role in drug design and lead optimization. Although ligand flexibility is now included in most docking programs, a complicating factor in structure-based drug design is the induced-fit upon ligand binding. The best currently available approach to incorporate protein fluctuations in ligand docking and scoring is the use of multiple receptor conformations. However, it remains an open question how these structures should be generated and used. We present and evaluate a novel methodology to incorporate receptor flexibility in ligand docking and virtual screening of the cAPK kinase. An ensemble of representative receptor backbone conformations of the ligand binding-pocket is generated using flexibility predictions based on normal mode analysis. Each ensemble conformation is complexed with known binders spanning different chemotypes, and the binding-pocket side-chains + ligand are subjected to a stochastic global energy optimization. Complexes are ranked by energy including terms for entropy and solvation, and the lowest energy complex per ligand is used to perform ligand docking and small-scale virtual screening using a 1000-compound library seeded with known binders. Improvements with respect to the single-receptor procedure for cross-docking results and enrichment factors are reported.