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Recent Insights from Molecular Dynamics Simulations for G Protein-Coupled Receptor Drug Discovery
Open AccessArticle

A Molecular Dynamics Study of Vasoactive Intestinal Peptide Receptor 1 and the Basis of Its Therapeutic Antagonism

1
Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland
2
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université libre de Bruxelles, B-1070 Brussels, Belgium
3
Faculty of Physics, University of Warsaw, 02-093 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(18), 4348; https://doi.org/10.3390/ijms20184348
Received: 30 June 2019 / Revised: 30 July 2019 / Accepted: 20 August 2019 / Published: 5 September 2019
(This article belongs to the Special Issue Computer Simulation on Membrane Receptors)
Vasoactive intestinal peptide receptor 1 (VPAC1) is a member of a secretin-like subfamily of G protein-coupled receptors. Its endogenous neuropeptide (VIP), secreted by neurons and immune cells, modulates various physiological functions such as exocrine and endocrine secretions, immune response, smooth muscles relaxation, vasodilation, and fetal development. As a drug target, VPAC1 has been selected for therapy of inflammatory diseases but drug discovery is still hampered by lack of its crystal structure. In this study we presented the homology model of this receptor constructed with the well-known web service GPCRM. The VPAC1 model is composed of extracellular and transmembrane domains that form a complex with an endogenous hormone VIP. Using the homology model of VPAC1 the mechanism of action of potential drug candidates for VPAC1 was described. Only two series of small-molecule antagonists of confirmed biological activity for VPAC1 have been described thus far. Molecular docking and a series of molecular dynamics simulations were performed to elucidate their binding to VPAC1 and resulting antagonist effect. The presented work provides the basis for the possible binding mode of VPAC1 antagonists and determinants of their molecular recognition in the context of other class B GPCRs. Until the crystal structure of VPAC1 will be released, the presented homology model of VPAC1 can serve as a scaffold for drug discovery studies and is available from the author upon request. View Full-Text
Keywords: G protein-coupled receptors; vasoactive intestinal peptide receptor 1; VPAC1; VIPR1; VIP; PACAP; homology modeling; molecular dynamics; GPCRM; gut hormone receptors; GPCR activation; antagonist; agonist G protein-coupled receptors; vasoactive intestinal peptide receptor 1; VPAC1; VIPR1; VIP; PACAP; homology modeling; molecular dynamics; GPCRM; gut hormone receptors; GPCR activation; antagonist; agonist
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MDPI and ACS Style

Latek, D.; Langer, I.; Krzysko, K.A.; Charzewski, L. A Molecular Dynamics Study of Vasoactive Intestinal Peptide Receptor 1 and the Basis of Its Therapeutic Antagonism. Int. J. Mol. Sci. 2019, 20, 4348.

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