title: In silico characterization of binding mode of CCR8 inhibitor: homology modeling, docking and membrane based MD simulation study.
abstract: Human CC-chemokine receptor 8 (CCR8) is a crucial drug target in asthma that belongs to G-protein-coupled receptor superfamily, which is characterized by seven transmembrane helices. To date, there is no X-ray crystal structure available for CCR8; this hampers active research on the target. Molecular basis of interaction mechanism of antagonist with CCR8 remains unclear. In order to provide binding site information and stable binding mode, we performed modeling, docking and molecular dynamics (MD) simulation of CCR8. Docking study of biaryl-ether-piperidine derivative (13C) was performed inside predefined CCR8 binding site to get the representative conformation of 13C. Further, MD simulations of receptor and complex (13C-CCR8) inside dipalmitoylphosphatidylcholine lipid bilayers were performed to explore the effect of lipids. Results analyses showed that the Gln91, Tyr94, Cys106, Val109, Tyr113, Cys183, Tyr184, Ser185, Lys195, Thr198, Asn199, Met202, Phe254, and Glu286 were conserved in both docking and MD simulations. This indicated possible role of these residues in CCR8 antagonism. However, experimental mutational studies on these identified residues could be effective to confirm their importance in CCR8 antagonism. Furthermore, calculated Coulombic interactions represented the crucial roles of Glu286, Lys195, and Tyr113 in CCR8 antagonism. Important residues identified in this study overlap with the previous non-peptide agonist (LMD-009) binding site. Though, the non-peptide agonist and currently studied inhibitor (13C) share common substructure, but they differ in their effects on CCR8. So, to get more insight into their agonist and antagonist effects, further side-by-side experimental studies on both agonist (LMD-009) and antagonist (13C) are suggested.
authors.affiliation: a Department of Life Sciences, College of BioNano Technology , Gachon University , 1342 Seongnamdaero, Sujeong-gu, Seongnam-si , Gyeonggi-do 461-701 , Republic of Korea.
authors.forename: Changdev G
authors.initials: CG
authors.lastname: Gadhe
authors.affiliation: b Department of Bio-New Drug Development, College of Medicine , Chosun University , Gwangju 501-759 , Republic of Korea.
authors.forename: Anand
authors.initials: A
authors.lastname: Balupuri
authors.affiliation: b Department of Bio-New Drug Development, College of Medicine , Chosun University , Gwangju 501-759 , Republic of Korea.|c Department of Cellular Molecular Medicine, College of Medicine , Chosun University , Gwangju 501-759 , Republic of Korea.
authors.forename: Seung Joo
authors.initials: SJ
authors.lastname: Cho
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D055808:Drug Discovery; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D021281:Quantitative Structure-Activity Relationship; D054401:Receptors, CCR8 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D015203:Reproducibility of Results; D016415:Sequence Alignment
chemical_list: D008024:Ligands; D054401:Receptors, CCR8
keywords: CCR8; MD simulation; docking; homology modeling; membrane protein