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Molecular Simulation of αvβ6 Integrin Inhibitors

Guest, Ellen E.; Oatley, Steven A.; Macdonald, Simon J. F.; Hirst, Jonathan D.

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Authors

Ellen E. Guest

Steven A. Oatley

Simon J. F. Macdonald



Abstract

The urgent need for new treatments for the chronic lung disease idiopathic pulmonary fibrosis (IPF) motivates research into antagonists of the RGD binding integrin αvβ6, a protein linked to the initiation and progression of the disease. Molecular dynamics (MD) simulations of αvβ6 in complex with its natural ligand, pro-TGF-β1, show the persistence over time of a bidentate Arg-Asp ligand-receptor interaction and a metal chelate interaction between an aspartate on the ligand and an Mg2+ ion in the active site. This is typical of RGD binding ligands. Additional binding site interactions, which are not observed in the static crystal structure, are also identified. We investigate an RGD mimetic, which serves as a framework for a series of potential αvβ6 antagonists. The scaffold includes a derivative of the widely utilized 1,8-naphthyridine moiety, for which we present force field parameters, to enable MD and relative free energy perturbation (FEP) simulations. The MD simulations highlight the importance of hydrogen bonding and cation-π interactions. The FEP calculations predict relative binding affinities, within 1.5 kcal mol-1, on average, of experiments.

Citation

Guest, E. E., Oatley, S. A., Macdonald, S. J. F., & Hirst, J. D. (2020). Molecular Simulation of αvβ6 Integrin Inhibitors. Journal of Chemical Information and Modeling, 60(11), 5487-5498. https://doi.org/10.1021/acs.jcim.0c00254

Journal Article Type Article
Acceptance Date May 18, 2020
Online Publication Date May 18, 2020
Publication Date Nov 23, 2020
Deposit Date May 29, 2020
Publicly Available Date May 19, 2021
Journal Journal of chemical information and modeling
Print ISSN 1549-9596
Electronic ISSN 1549-960X
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 60
Issue 11
Pages 5487-5498
DOI https://doi.org/10.1021/acs.jcim.0c00254
Public URL https://nottingham-repository.worktribe.com/output/4530459
Publisher URL https://pubs.acs.org/doi/10.1021/acs.jcim.0c00254
Additional Information This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Information and Modeling,copyright© American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jcim.0c00254

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