J Med Chem. 2008 Jun 26;51(12):3499-506. Epub 2008 Jun 3.

Protein-ligand docking accounting for receptor side chain and global flexibility in normal modes: evaluation on kinase inhibitor cross docking.

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School of Engineering and Science, Jacobs University Bremen, Campus Ring 6, D-28759 Bremen, Germany.

Abstract

Efficient treatment of conformational changes during docking of drug-like ligands to receptor molecules is a major computational challenge. A new docking methodology has been developed that includes ligand flexibility and both global backbone flexibility and side chain flexibility of the protein receptor. Whereas side chain flexibility is based on a discrete rotamer approach, global backbone conformational changes are modeled by relaxation in a few precalculated soft collective degrees of freedom of the receptor. The method was applied to docking of several known cyclin dependent kinase 2 inhibitors to the unbound kinase structure and to cross-docking of inhibitors to several bound kinase structures. Significant improvement of ranking and deviation of predicted binding geometries from experiment was obtained compared to docking to a rigid receptor. The inclusion of only the soft collective degrees of freedom during docking resulted in improved docking performance at a very modest increase (doubling) of the computational demand.

PMID:: 18517186; [PubMed - indexed for MEDLINE]

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