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

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.