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X-ray Crystallography, DFT Calculations and Molecular Docking of Indole-Arylpiperazine Derivatives as ?1A-Adrenoceptor Antagonists.

ABSTRACT: 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···? 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-?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.

SUBMITTER: Xu W

PROVIDER: S-EPMC6332402 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Xu Wei W Huang Jun-Jun JJ Shao Bin-Hao BH Xu Xing-Jie XJ Jiang Ren-Wang RW Yuan Mu M

Molecules (Basel, Switzerland) 20151030 11

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 ...[more]

PMID: 26528963

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Project description:Crystals of Zn2+/Mn2+ yeast enolase with the inhibitor PhAH (phosphonoacetohydroxamate) were grown under conditions with a slight preference for binding of Zn2+ at the higher affinity site, site I. The structure of the Zn2+/Mn2+-PhAH complex was solved at a resolution of 1.54 A, and the two catalytic metal binding sites, I and II, show only subtle displacement compared to that of the corresponding complex with the native Mg2+ ions. Low-temperature echo-detected high-field (W-band, 95 GHz) EPR (electron paramagnetic resonance) and 1H ENDOR (electron-nuclear double resonance) were carried out on a single crystal, and rotation patterns were acquired in two perpendicular planes. Analysis of the rotation patterns resolved a total of six Mn2+ sites, four symmetry-related sites of one type and two out of the four of the other type. The observation of two chemically inequivalent Mn2+ sites shows that Mn2+ ions populate both sites I and II and the zero-field splitting (ZFS) tensors of the Mn2+ in the two sites were determined. The Mn2+ site with the larger D value was assigned to site I based on the 1H ENDOR spectra, which identified the relevant water ligands. This assignment is consistent with the seemingly larger deviation of site I from octahedral symmetry, compared to that of site II. The ENDOR results gave the coordinates of the protons of two water ligands, and adding them to the crystal structure revealed their involvement in a network of H bonds stabilizing the binding of the metal ions and PhAH. Although specific hyperfine interactions with the inhibitor were not determined, the spectroscopic properties of the Mn2+ in the two sites were consistent with the crystal structure. Density functional theory (DFT) calculations carried out on a cluster representing the catalytic site, with Mn2+ in site I and Zn2+ in site II, and vice versa, gave overestimated D values on the order of the experimental ones, although the larger D value was found for Mn2+ in site II rather than in site I. This discrepancy was attributed to the high sensitivity of the ZFS parameters to the Mn-O bond lengths and orientations, such that small, but significant, differences between the optimized and crystal structures alter the ZFS considerably, well above the difference between the two sites.

Dataset Information

X-ray Crystallography, DFT Calculations and Molecular Docking of Indole-Arylpiperazine Derivatives as ?1A-Adrenoceptor Antagonists.

Publications

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

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