A Multiscale Simulation Approach to Modeling Drug–Protein Binding Kinetics

• DOI: 10.1021/acs.jctc.8b00687
• Publication Date: 2018-09-13T04:05:27Z
• Authors: Susanta Haldar; Federico Comitani; Giorgio Saladino; Christopher Woods; Marc W. van der Kamp; Adrian J. Mulholland; Francesco Luigi G...
• Keywords: Receptor–ligand kinetics; Molecular mechanics; Molecular binding

Drug-target binding kinetics has recently emerged as a sometimes critical determinant of in vivo efficacy and toxicity. Its rational optimization to improve potency or reduce side effects drugs is, however, extremely difficult. Molecular simulations can play crucial role identifying features properties small ligands their protein targets affecting the kinetics, but significant challenges include long time scales involved (un)binding events limited accuracy empirical atomistic force fields (lacking, e.g., changes electronic polarization). In an effort overcome these hurdles, we propose method that combines state-of-the-art enhanced sampling quantum mechanics/molecular mechanics (QM/MM) calculations at BLYP/VDZ level compute association free energy profiles characterize terms structure dynamics transition state ensemble. We test our combined approach on anticancer drug Imatinib Src kinase, well-characterized target for cancer therapy with complex mechanism involving conformational changes. The results indicate polarization along pathways, which affect predicted kinetics. This is likely be widespread importance targets.