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A multiscale simulation approach to modelling drug-protein binding kinetics

Research output: Contribution to journalArticle

Original languageEnglish
Number of pages9
JournalJournal of Chemical Theory and Computation
Early online date13 Sep 2018
DOIs
DateAccepted/In press - 12 Sep 2018
DateE-pub ahead of print (current) - 13 Sep 2018

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.

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via ACS at https://pubs.acs.org/doi/10.1021/acs.jctc.8b00687. Please refer to any applicable terms of use of the publisher.

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  • Supplementary information PDF

    Accepted author manuscript, 365 KB, PDF document

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