binding, thermodynamics, and selectivity of a non-peptide antagonist to the melanocortin-4 receptor

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ID: 236938
2018
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Abstract
The melanocortin-4 receptor (MC4R) is a potential drug target for treatment of obesity, anxiety, depression, and sexual dysfunction. Crystal structures for MC4R are not yet available, which has hindered successful structure-based drug design. Using microsecond-scale molecular-dynamics simulations, we have investigated selective binding of the non-peptide antagonist MCL0129 to a homology model of human MC4R (hMC4R). This approach revealed that, at the end of a multi-step binding process, MCL0129 spontaneously adopts a binding mode in which it blocks the agonistic-binding site. This binding mode was confirmed in subsequent metadynamics simulations, which gave an affinity for human hMC4R that matches the experimentally determined value. Extending our simulations of MCL0129 binding to hMC1R and hMC3R, we find that receptor subtype selectivity for hMC4R depends on few amino acids located in various structural elements of the receptor. These insights may support rational drug design targeting the melanocortin systems.
Reference Key
saleh2018frontiersbinding, Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Noureldin Saleh;Noureldin Saleh;Gunnar Kleinau;Gunnar Kleinau;Nicolas Heyder;Nicolas Heyder;Timothy Clark;Peter W. Hildebrand;Peter W. Hildebrand;Peter W. Hildebrand;Patrick Scheerer;Patrick Scheerer
Journal chemical research in chinese universities
Year 2018
DOI
10.3389/fphar.2018.00560
URL
https://www.frontiersin.org/article/10.3389/fphar.2018.00560/full
Keywords
ligand binding pharmacology

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