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Crystallographic and Theoretical Exploration of Weak Hydrogen Bonds in Arylmethyl N'-(adamantan-1-yl)piperidine-1-carbothioimidates and Molecular Docking Analysis.

ABSTRACT: Crystal structures of two potential chemotherapeutic agents, namely 4-nitrobenzyl N'-(adamantan-1-yl)piperidine-1-carbothioimidate 1 and 4-bromobenzyl N'-(adamantan-1-yl)piperidine-1-carbothioimidate 2, have been analyzed in detail. X-ray analysis reveals that the molecular conformations of these compounds are strikingly different. These two structures are compared with two of their closely related structures. In the related structures, morpholine replaces piperidine. Based on the Hirshfeld surface analysis and two-dimensional (2D) fingerprint plots, we describe the effects of piperidine/morpholine and Br/NO₂ groups on the intermolecular interactions. An analysis of the CLP-PIXEL energy provides insight into the energetics of the dimers observed in the title compounds and their related structures. Compound 1 stabilizes with bifurcated C-H···S, C-H···O, and O(lp)···C(π) interactions, whereas compound 2 stabilizes with C-H···N, C-H···Br, and C-H···C interactions. The energy frameworks for the crystal structures of the title compounds reveal differences. The atoms-in-molecules (AIM) analysis was performed to confirm the intermolecular interactions found in the crystal structures of 1 and 2. Additionally, docking analysis suggests that the title compounds bind at the active site of human sphingosine kinase 1, a well-known cancer target.

SUBMITTER: Al-Mutairi AA

PROVIDER: S-EPMC8529591 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Crystallographic and Theoretical Exploration of Weak Hydrogen Bonds in Arylmethyl N'-(adamantan-1-yl)piperidine-1-carbothioimidates and Molecular Docking Analysis.

Al-Mutairi Aamal A AA Alagappan Kowsalya K Blacque Olivier O Al-Alshaikh Monirah A MA El-Emam Ali A AA Percino M Judith MJ Thamotharan Subbiah S

ACS omega 20211007 41

Crystal structures of two potential chemotherapeutic agents, namely 4-nitrobenzyl N'-(adamantan-1-yl)piperidine-1-carbothioimidate 1 and 4-bromobenzyl N'-(adamantan-1-yl)piperidine-1-carbothioimidate 2, have been analyzed in detail. X-ray analysis reveals that the molecular conformations of these compounds are strikingly different. These two structures are compared with two of their closely related structures. In the related structures, morpholine replaces piperidine. ...[more]

PMID: 34693122

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Project description:Time-resolved Fourier transform infrared (FTIR) spectroscopy is a powerful tool to elucidate label-free the reaction mechanisms of proteins. After assignment of the absorption bands to individual groups of the protein, the order of events during the reaction mechanism can be monitored and rate constants can be obtained. Additionally, structural information is encoded into infrared spectra and can be decoded by combining the experimental data with biomolecular simulations. We have determined recently the infrared vibrations of GTP and guanosine diphosphate (GDP) bound to Gαi1, a ubiquitous GTPase. These vibrations are highly sensitive for the environment of the phosphate groups and thereby for the binding mode the GTPase adopts to enable fast hydrolysis of GTP. In this study we calculated these infrared vibrations from biomolecular simulations to transfer the spectral information into a computational model that provides structural information far beyond crystal structure resolution. Conformational ensembles were generated using 15 snapshots of several 100 ns molecular-mechanics/molecular-dynamics (MM-MD) simulations, followed by quantum-mechanics/molecular-mechanics (QM/MM) minimization and normal mode analysis. In comparison with other approaches, no time-consuming QM/MM-MD simulation was necessary. We carefully benchmarked the simulation systems by deletion of single hydrogen bonds between the GTPase and GTP through several Gαi1 point mutants. The missing hydrogen bonds lead to blue-shifts of the corresponding absorption bands. These band shifts for α-GTP (Gαi1-T48A), γ-GTP (Gαi1-R178S), and for both β-GTP/γ-GTP (Gαi1-K46A, Gαi1-D200E) were found in agreement in the experimental and the theoretical spectra. We applied our approach to open questions regarding Gαi1: we show that the GDP state of Gαi1 carries a Mg2+, which is not found in x-ray structures. Further, the catalytic role of K46, a central residue of the P-loop, and the protonation state of the GTP are elucidated.

Dataset Information

Crystallographic and Theoretical Exploration of Weak Hydrogen Bonds in Arylmethyl N'-(adamantan-1-yl)piperidine-1-carbothioimidates and Molecular Docking Analysis.

Publications

Crystallographic and Theoretical Exploration of Weak Hydrogen Bonds in Arylmethyl <i>N</i>'-(adamantan-1-yl)piperidine-1-carbothioimidates and Molecular Docking Analysis.

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