Protein−Ligand Docking Accounting for Receptor Side Chain and Global Flexibility in Normal Modes: Evaluation on Kinase Inhibitor Cross Docking

@article{citeulike:2906946, abstract = {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.}, address = {School of Engineering and Science, Jacobs University Bremen, Campus Ring 6, D-28759 Bremen, Germany}, author = {May, Andreas and Zacharias, Martin }, citeulike-article-id = {2906946}, doi = {http://dx.doi.org/10.1021/jm800071v}, journal = {J. Med. Chem.}, keywords = {enm\_application\_docking}, month = {June}, number = {12}, pages = {3499--3506}, posted-at = {2008-07-25 09:16:38}, priority = {2}, title = {Protein\&\#x2212;Ligand Docking Accounting for Receptor Side Chain and Global Flexibility in Normal Modes: Evaluation on Kinase Inhibitor Cross Docking}, url = {http://dx.doi.org/10.1021/jm800071v}, volume = {51}, year = {2008} }

TY - JOUR ID - citeulike:2906946 L3 - citeulike-article-id:2906946 N2 - 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. IS - 12 JF - J. Med. Chem. AD - School of Engineering and Science, Jacobs University Bremen, Campus Ring 6, D-28759 Bremen, Germany EP - 3506 TI - Protein−Ligand Docking Accounting for Receptor Side Chain and Global Flexibility in Normal Modes: Evaluation on Kinase Inhibitor Cross Docking VL - 51 SP - 3499 KW - enm_application_docking AU - May, Andreas AU - Zacharias, Martin PY - 2008/06/26/ UR - http://dx.doi.org/10.1021/jm800071v ER -