title: X-ray Crystallography, DFT Calculations and Molecular Docking of Indole-Arylpiperazine Derivatives as α1A-Adrenoceptor Antagonists.
abstract: Indole-arylpiperazine derivatives have exhibited good selectivity for the α1A-adrenoceptor, but the structure-activity-binding mechanism relationship remains unclear. In the current study, three compounds (1, 2 and 3) were investigated through single-crystal X-ray diffraction analysis, density functional theory (DFT) calculations and molecular docking using a homology model of the α1A receptor. Compounds 1 and 3 form H-bonds networks to stabilize their three-dimensional structures, while C-H···π interactions play a significant role in the packing of 2. Based on DFT-optimized conformations, the HOMO-LUMO energy gaps and molecular electrostatic potential (MEP) were theoretically calculated at the B3LYP/6-311G (d, p) level of theory. Chemical reactivity increases in the order of 3 < 2 < 1, and the maximum positive region of the MEP maps is mainly localized over the NH group. The binding mechanisms of ligand-α1A-adrenoceptor complexes were illustrated by molecular docking. Binding to Gln177 of the second extracellular loop region via hydrogen bonds is likely to be essential for α1A-selective antagonists. The present work sheds light on the studies of structure-activity-binding mechanism and aids in the design of α1A antagonists with high selectivity.
authors.affiliation: Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, China. xwnail2003@163.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, China. huangjunjun1985@sina.com.
authors.forename: Jun-Jun
authors.initials: JJ
authors.lastname: Huang
authors.affiliation: Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, China. sbh1539@sina.cn.
authors.forename: Bin-Hao
authors.initials: BH
authors.lastname: Shao
authors.affiliation: Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, China. xuxingjie2015@163.com.
authors.forename: Xing-Jie
authors.initials: XJ
authors.lastname: Xu
authors.affiliation: School of Pharmaceutical Sciences, Jinan University, Guangzhou 510632, China. rwjiang2008@126.com.
authors.forename: Ren-Wang
authors.initials: RW
authors.lastname: Jiang
authors.affiliation: Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, China. mryuanmu838@sina.com.
authors.forename: Mu
authors.initials: M
authors.lastname: Yuan
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D008024:Ligands; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D000077489:Piperazine
keywords: DFT calculations; indole-arylpiperazine; molecular docking; single-crystal; α1A-adrenoceptor