Molecular Simulation of αvβ6 Integrin Inhibitors

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

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