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Development of efficient docking strategies and structure-activity relationship study of the c-Met type II inhibitors. | LitMetric

Development of efficient docking strategies and structure-activity relationship study of the c-Met type II inhibitors.

J Mol Graph Model

Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China. Electronic address:

Published: August 2017

AI Article Synopsis

  • c-Met is a key receptor linked to cancer treatments, and this study explores factors affecting the accuracy of predicting how well specific inhibitors bind to it.
  • The research highlights that the choice of force fields, the flexibility of the protein, and the binding site's conformation have a major impact on the prediction accuracy, while the methods used for sampling and docking have less influence.
  • Findings suggest that type II c-Met inhibitors have a high binding affinity due to their linear shape, hydrophobic characteristics, and specific hydrogen bonds, providing a foundation for better computational design of these inhibitors.

Article Abstract

c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In the present study, we systematically investigated the influence of a range of parameters on the correlation between experimental and calculated binding free energies of type II c-Met inhibitors. We especially focused on evaluating the impact of different force fields, binding energy calculation methods, docking protocols, conformation sampling strategies, and conformations of the binding site captured in several crystallographic structures. Our results suggest that the force fields, the protein flexibility, and the selected conformation of the binding site substantially influence the correlation coefficient, while the sampling strategies and ensemble docking only mildly affect the prediction accuracy. Structure-activity relationship study suggests that the structural determinants to the high binding affinity of the type II inhibitors originate from its overall linear shape, hydrophobicity, and two conserved hydrogen bonds. Results from this study will form the basis for establishing an efficient computational docking approach for c-Met type II inhibitors design.

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Source
http://dx.doi.org/10.1016/j.jmgm.2017.04.004DOI Listing

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