Binding, Thermodynamics, and Selectivity of a Non-peptide Antagonist to the Melanocortin-4 Receptor
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, w...
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Frontiers Media S.A.
2018-06-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2018.00560/full |
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doaj-6aa741c50a304af09e5f0b05cbb74b762020-11-24T23:15:44ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-06-01910.3389/fphar.2018.00560370881Binding, Thermodynamics, and Selectivity of a Non-peptide Antagonist to the Melanocortin-4 ReceptorNoureldin Saleh0Noureldin Saleh1Gunnar Kleinau2Gunnar Kleinau3Nicolas Heyder4Nicolas Heyder5Timothy Clark6Peter W. Hildebrand7Peter W. Hildebrand8Peter W. Hildebrand9Patrick Scheerer10Patrick Scheerer11Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Institute of Medical Physics and Biophysics, Berlin, GermanyComputational Modelling and Dynamics of Molecular Complexes, Berlin, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Institute of Medical Physics and Biophysics, Berlin, GermanyGroup Protein X-ray Crystallography and Signal Transduction, Berlin, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Institute of Medical Physics and Biophysics, Berlin, GermanyGroup Protein X-ray Crystallography and Signal Transduction, Berlin, GermanyComputer-Chemie-Centrum, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Institute of Medical Physics and Biophysics, Berlin, GermanyComputational Modelling and Dynamics of Molecular Complexes, Berlin, GermanyInstitute of Medical Physics and Biophysics, Leipzig University, Leipzig, GermanyCharité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Institute of Medical Physics and Biophysics, Berlin, GermanyGroup Protein X-ray Crystallography and Signal Transduction, Berlin, GermanyThe 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.https://www.frontiersin.org/article/10.3389/fphar.2018.00560/fullMC4Rmelanocortin-4 receptormelanocortin-receptorsligand bindingligand selectivitymolecular dynamics |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 Binding, Thermodynamics, and Selectivity of a Non-peptide Antagonist to the Melanocortin-4 Receptor Frontiers in Pharmacology MC4R melanocortin-4 receptor melanocortin-receptors ligand binding ligand selectivity molecular dynamics |
| author_facet |
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 |
| author_sort |
Noureldin Saleh |
| title |
Binding, Thermodynamics, and Selectivity of a Non-peptide Antagonist to the Melanocortin-4 Receptor |
| title_short |
Binding, Thermodynamics, and Selectivity of a Non-peptide Antagonist to the Melanocortin-4 Receptor |
| title_full |
Binding, Thermodynamics, and Selectivity of a Non-peptide Antagonist to the Melanocortin-4 Receptor |
| title_fullStr |
Binding, Thermodynamics, and Selectivity of a Non-peptide Antagonist to the Melanocortin-4 Receptor |
| title_full_unstemmed |
Binding, Thermodynamics, and Selectivity of a Non-peptide Antagonist to the Melanocortin-4 Receptor |
| title_sort |
binding, thermodynamics, and selectivity of a non-peptide antagonist to the melanocortin-4 receptor |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Pharmacology |
| issn |
1663-9812 |
| publishDate |
2018-06-01 |
| description |
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. |
| topic |
MC4R melanocortin-4 receptor melanocortin-receptors ligand binding ligand selectivity molecular dynamics |
| url |
https://www.frontiersin.org/article/10.3389/fphar.2018.00560/full |
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