Steered molecular dynamics simulations for uncovering the molecular mechanisms of drug dissociation and for drug screening: A test on the focal adhesion kinase

Journal of Computational Chemistry
Chung F Wong

Abstract

Drug-binding kinetics could play important roles in determining the efficacy of drugs and has caught the attention of more drug designers. Using the dissociation of 1H-pyrrolo[2,3-b]-pyridines from the focal adhesion kinase as an example, this work finds that steered molecular dynamics simulations could help screen compounds with long-residence times. It also reveals a two-step mechanism of ligand dissociation resembling the release of ADP from protein kinase A reported earlier. A phenyl group attaching to the pyrrole prolongs residence time by creating a large activation barrier for transition from the bound to the intermediate state when it becomes exposed to the solvent. Principal component analysis shows that ligand dissociation does not couple with large-scale collective motions of the protein involving many of its amino acids. Rather, a small subset of amino acids dominates. Some of these amino acids do not contact the ligands directly along the dissociation pathways and could exert long-range allosteric effects. © 2018 Wiley Periodicals, Inc.

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Citations

Nov 23, 2019·Journal of Biomolecular Structure & Dynamics·Madhulata Kumari, Naidu Subbarao
Nov 9, 2020·Bioorganic & Medicinal Chemistry Letters·Ajay PalGemma K Kinsella
Oct 3, 2020·Chemical Reviews·Sergio Decherchi, Andrea Cavalli
Sep 12, 2019·Journal of Chemical Theory and Computation·Indrajit Deb, Aaron T Frank
Feb 28, 2019·Journal of Chemical Theory and Computation·Wanli YouChia-En A Chang
Nov 4, 2021·Expert Opinion on Drug Discovery·Qianqian ZhangHuanxiang Liu

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