X-ray Crystallography, DFT Calculations and Molecular Docking of Indole-Arylpiperazine Derivatives as α1A-Adrenoceptor Antagonists
| Autor: | Bin-Hao Shao, Xingjie Xu, Mu Yuan, Ren-Wang Jiang, Junjun Huang, Wei Xu |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Stereochemistry Molecular Conformation Pharmaceutical Science DFT calculations Crystallography X-Ray Ligands Molecular Docking Simulation Article Piperazines Analytical Chemistry lcsh:QD241-441 α1A-adrenoceptor Structure-Activity Relationship lcsh:Organic chemistry Receptors Adrenergic alpha-1 Drug Discovery Structure–activity relationship Homology modeling Physical and Theoretical Chemistry Piperazine Indole test Chemistry Hydrogen bond Organic Chemistry Hydrogen Bonding molecular docking indole-arylpiperazine single-crystal Crystallography Chemistry (miscellaneous) Searching the conformational space for docking Adrenergic alpha-1 Receptor Antagonists Molecular Medicine Density functional theory Selectivity |
| Zdroj: | Molecules Volume 20 Issue 11 Pages 19674-19689 Molecules, Vol 20, Iss 11, Pp 19674-19689 (2015) Molecules; Volume 20; Issue 11; Pages: 19674-19689 |
| ISSN: | 1420-3049 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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