X-ray Crystallography, DFT Calculations and Molecular Docking of Indole-Arylpiperazine Derivatives as alpha(1A)-Adrenoceptor Antagonists

作者：Xu, Wei; Huang, Jun-Jun; Shao, Bin-Hao; Xu, Xing-Jie; Jiang, Ren-Wang; Yuan, Mu^*

来源：Molecules, 2015, 20(11): 19674-19689.

DOI：10.3390/molecules201119651

• indole-arylpiperazine
• single-crystal
• DFT calculations
• molecular docking
• alpha(1A)-adrenoceptor

Indole-arylpiperazine derivatives have exhibited good selectivity for the (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 (1A) receptor. Compounds 1 and 3 form H-bonds networks to stabilize their three-dimensional structures, while C-H<bold> interactions play a significant role in the packing of </bold>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-(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 (1A-)selective antagonists. The present work sheds light on the studies of structure-activity-binding mechanism and aids in the design of (1A) antagonists with high selectivity.

• 出版日期2015-11
• 单位广州医科大学; 暨南大学