title: Identification of potential CCR5 inhibitors through pharmacophore-based virtual screening, molecular dynamics simulation and binding free energy analysis.
abstract: CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), plays a vital role in inflammatory responses to infection. Alterations in the expression of CCR5 have been correlated with disease progression in many types of cancers. The idea of using CCR5 as a target for therapeutic intervention has been demonstrated to prevent disease progression. To date, only a few compounds have been reported as CCR5 inhibitors. In this study, a series of CCR5 antagonists were used to construct pharmacophore models. Then the optimal model was utilized as a 3D query to identify novel chemical entities from structural databases. After refinement by molecular docking, drug-likeness analysis, molecular dynamics simulations (MDS) and binding free energy analysis, three potential inhibitors (25, 29 and 45) were identified. MD simulations suggested that the screened compounds retained the important common binding mode known for CCR5 inhibitors (maraviroc and nifeviroc), which occupied the bottom of a pocket and stabilized the conformation of CCR5. During the binding process, van der Waals interactions provided the substantial driving force. The most favorable contributions were from Tyr37, Trp86, Tyr89, Tyr108, Phe109, Phe112, Gln194, Thr195, Ile198, Trp248, Tyr251, Leu255, Thr259, Met279, Glu283 and Met287. The above results suggest that the hybrid strategy would provide a basis for rational drug design.
authors.affiliation: Key Laboratory of Biorheological Science and Technology (Ministry of Education), Research Center of Bioinspired Material Science and Engineering, Bioengineering College, Chongqing University, Chongqing 400044, China. wyl@cqu.edu.cn.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China. zhlin@cqut.edu.cn.
authors.forename: Mao
authors.initials: M
authors.lastname: Shu
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China. zhlin@cqut.edu.cn.
authors.forename: Yuanqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China. zhlin@cqut.edu.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Key Laboratory of Biorheological Science and Technology (Ministry of Education), Research Center of Bioinspired Material Science and Engineering, Bioengineering College, Chongqing University, Chongqing 400044, China. wyl@cqu.edu.cn.
authors.forename: Yuanliang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Biorheological Science and Technology (Ministry of Education), Research Center of Bioinspired Material Science and Engineering, Bioengineering College, Chongqing University, Chongqing 400044, China. wyl@cqu.edu.cn.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Luo
authors.affiliation: School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China. zhlin@cqut.edu.cn and College of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400044, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Lin
mesh_terms: D001665:Binding Sites; D065100:CCR5 Receptor Antagonists / Q000737:chemistry*; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D019713:Receptors, CCR5 / Q000737:chemistry*; D015203:Reproducibility of Results
chemical_list: D065100:CCR5 Receptor Antagonists; D008024:Ligands; D019713:Receptors, CCR5