Abstract
Molecular modeling of G-protein coupled receptors (GPCRs) remains a challenge due to the limited availability of structural information for the receptors. Molecular modeling approaches for melanocortin receptors (MCRs) fall into three categories: structurebased, ligand-based, and proteochemometric. Homology modeling combined with the information obtained from site-directed mutagenesis of receptors, recombined chimeric mutations of receptors and the structures of melanocortin type 4 receptor (MC4R) peptide ligands, has provided insights on detailed ligand-receptor interactions. Still, homology models based on the structures of bacteriorhodopsin (bR) or bovine rhodopsin as templates have not reached atomic level accuracy, making them unsuitable for rational drug design. On the other hand, availability of a large number of potent ligands of MCRs, especially those for the therapeutically important MC4R, has fueled ligand-based approaches, including automated pharmacophore query optimization and pharmacophorebased virtual screening. Proteochemometrics, a novel technology for the analysis of intermolecular interactions between ligand and receptor, has also shown great value in obtaining detailed informaton on molecular recognition and providing guidance to ligand design. In this review, the strengths and limitations of homology modeling, pharmacophore modeling and proteochemometrics modeling of MCRs are evaluated.
Keywords: double loop cross validation, Pharmacophore modeling, bovine rhodopsin, GLY-GLY combination, MSH analogues
Current Topics in Medicinal Chemistry
Title: Molecular Modeling of Melanocortin Receptors
Volume: 7 Issue: 11
Author(s): Hongmao Sun and David Fry
Affiliation:
Keywords: double loop cross validation, Pharmacophore modeling, bovine rhodopsin, GLY-GLY combination, MSH analogues
Abstract: Molecular modeling of G-protein coupled receptors (GPCRs) remains a challenge due to the limited availability of structural information for the receptors. Molecular modeling approaches for melanocortin receptors (MCRs) fall into three categories: structurebased, ligand-based, and proteochemometric. Homology modeling combined with the information obtained from site-directed mutagenesis of receptors, recombined chimeric mutations of receptors and the structures of melanocortin type 4 receptor (MC4R) peptide ligands, has provided insights on detailed ligand-receptor interactions. Still, homology models based on the structures of bacteriorhodopsin (bR) or bovine rhodopsin as templates have not reached atomic level accuracy, making them unsuitable for rational drug design. On the other hand, availability of a large number of potent ligands of MCRs, especially those for the therapeutically important MC4R, has fueled ligand-based approaches, including automated pharmacophore query optimization and pharmacophorebased virtual screening. Proteochemometrics, a novel technology for the analysis of intermolecular interactions between ligand and receptor, has also shown great value in obtaining detailed informaton on molecular recognition and providing guidance to ligand design. In this review, the strengths and limitations of homology modeling, pharmacophore modeling and proteochemometrics modeling of MCRs are evaluated.
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Cite this article as:
Hongmao Sun and David Fry , Molecular Modeling of Melanocortin Receptors, Current Topics in Medicinal Chemistry 2007; 7 (11) . https://dx.doi.org/10.2174/156802607780906573
DOI https://dx.doi.org/10.2174/156802607780906573 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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