Simulating dynamic interaction between diazepam and ethanol targeting the GABAA receptor via in silico model.

Lele Wang, Ruili Wang, Qian Zheng, Xiukun Yao, Chao Zhang, Shanlin Fu, Zhiwen Wei, Keming Yun, Zhongyuan Guo

Neurotoxicology 2023 Mar

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Combined diazepam-ethanol poisoning is common in forensic toxicology. Both diazepam and ethanol can inhibit the central nervous system via the γ-aminobutyric acid (GABA) ligand gated chloride ion channel, GABAA Receptor (GABAAR). As the common target of diazepam and ethanol, whether GABAAR is the key target of their combined action remains unclear. This study aimed to explore their interaction based on the synergistic mechanisms between diazepam and ethanol targeting the GABAAR. Four models were built in silico based on the crystal structure of GABAAR. Molecular dynamic processes of the four models were simulated by the GPU-accelerated pmemd.cuda program in the Amber18 package. Results showed that ethanol inclined to combine the adjacent GABA or diazepam sites, minimized fluctuations of the root-mean-square deviation (RMSD) in the molecular dynamic process of GABA or diazepam binding the GABAAR, and increased the release of binding energy of GABA or diazepam binding the GABAAR. Results also showed that diazepam had less effect on the RMSD fluctuation or the binding energy release of GABA binding GABAAR. The formation of complex of diazepam and GABAAR could minimize the RMSD fluctuation and increase binding energy release of ethanol binding GABAAR. Thus, ethanol, bridging GABA and diazepam, could strengthen the complex of GABA binding the GABAAR, as well as the complex of diazepam binding the GABAAR. However, whether diazepam binds GABAAR or not, it cannot affect GABA binding the GABAAR; and yet the complex of diazepam and GABAAR can stabilize the complex of ethanol and GABAAR. Copyright © 2023 Elsevier B.V. All rights reserved.

Citation

Lele Wang, Ruili Wang, Qian Zheng, Xiukun Yao, Chao Zhang, Shanlin Fu, Zhiwen Wei, Keming Yun, Zhongyuan Guo. Simulating dynamic interaction between diazepam and ethanol targeting the GABAA receptor via in silico model. Neurotoxicology. 2023 Mar;95:136-143