Pharmacophore-directed homology modeling and molecular dynamics simulation of G protein-coupled receptor: study of possible binding modes of 5-HT2C receptor agonists.
A new pharmacophore-based modeling procedure, including homology modeling, pharmacophore study, flexible molecular docking, and long-time molecular dynamics (MD) simulations, was employed to construct the structure of the human 5-HT(2C) receptor and determine the characteristics of binding modes of 5-HT(2C) receptor agonists. An agonist-receptor complex has been constructed based on homology modeling and a pharmacophore hypothesis model based on some high active compounds. Then MD simulations of the ligand-receptor complex in an explicit membrane environment were carried out. The conformation of the 5-HT(2C) receptor during MD simulation was explored, and the stable binding modes of the studied agonist were determined. Flexible molecular docking of several structurally diverse agonists of the human 5-HT(2C) receptor was carried out, and the general binding modes of these agonists were investigated. According to the models presented in this work and the results of Flexi-Dock, the involvement of the amino acid residues Asp134, Ser138, Asn210, Asn331, Tyr358, Ile131, Ser132, Val135,Thr139, Ile189, Val202, Val208, Leu209, Phe214, Val215, Gly218, Ser219, Phe223, Trp324, Phe327, and Phe328 in agonist recognition was studied. The obtained binding modes of the human 5-HT(2C) receptor agonists have good agreement with the site-directed mutagenesis data and other studies.
Zuo
Zhili
Z
Drug Discovery and Design Centre, State Key Laboratory of Drug Research, Shanghai Institute of MateriaMedica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
Chen
Gang
G
Luo
Xiaomin
X
Puah
Chummok
C
Zhu
Weiliang
W
Chen
Kaixian
K
Jiang
Hualiang
H
D000595:Amino Acid Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry* / Q000378:metabolism; D011955:Receptors, Drug; D012243:Rhodopsin / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D008051:Lipid Bilayers; D044405:Receptor, Serotonin, 5-HT2C; D011955:Receptors, Drug; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D012243:Rhodopsin