Haldar, S;
Comitani, F;
Saladino, G;
Woods, C;
van der Kamp, MW;
Mulholland, AJ;
Gervasio, FL;
(2018)
A Multiscale Simulation Approach to Modeling Drug–Protein Binding Kinetics.
Journal of Chemical Theory and Computation
, 14
(11)
pp. 6093-6101.
10.1021/acs.jctc.8b00687.
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Abstract
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 of drugs is, however, extremely difficult. Molecular simulations can play a crucial role in identifying features and properties of small ligands and their protein targets affecting the binding kinetics, but significant challenges include the long time scales involved in (un)binding events and the limited accuracy of empirical atomistic force fields (lacking, e.g., changes in electronic polarization). In an effort to overcome these hurdles, we propose a method that combines state-of-the-art enhanced sampling simulations and quantum mechanics/molecular mechanics (QM/MM) calculations at the BLYP/VDZ level to compute association free energy profiles and characterize the binding kinetics in terms of structure and dynamics of the transition state ensemble. We test our combined approach on the binding of the anticancer drug Imatinib to Src kinase, a well-characterized target for cancer therapy with a complex binding mechanism involving significant conformational changes. The results indicate significant changes in polarization along the binding pathways, which affect the predicted binding kinetics. This is likely to be of widespread importance in binding of ligands to protein targets.
Type: | Article |
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Title: | A Multiscale Simulation Approach to Modeling Drug–Protein Binding Kinetics |
Location: | United States |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1021/acs.jctc.8b00687 |
Publisher version: | http://dx.doi.org/10.1021/acs.jctc.8b00687 |
Language: | English |
Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
URI: | https://discovery.ucl.ac.uk/id/eprint/10059484 |
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