X-ray Crystallography, DFT Calculations and Molecular Docking of Indole-Arylpiperazine Derivatives as α1A-Adrenoceptor Antagonists

Molecules

Wei Xu²  Jun-Jun Huang²  Bin-Hao Shao²  Xing-Jie Xu²  Ren-Wang Jiang¹  Mu Yuan² 

[1] School of Pharmaceutical Sciences, Jinan University, Guangzhou 510632, China;Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, China;

关键词: indole-arylpiperazine;    single-crystal;    DFT calculations;    molecular docking;    α_1A-adrenoceptor;   

DOI  :  10.3390/molecules201119651

来源: mdpi

【 摘 要 】

Indole-arylpiperazine derivatives have exhibited good selectivity for the α_1A-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 α_1A 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-α_1A-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 α_1A-selective antagonists. The present work sheds light on the studies of structure-activity-binding mechanism and aids in the design of α_1A antagonists with high selectivity.

【 授权许可】

CC BY   
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