Investigation of [3H]diazepam derivatives as allosteric modulators of GABAA receptor α1β2γ2 subtypes: combination of molecular docking/dynamic simulations, pharmacokinetics/drug-likeness prediction, and QSAR analysis

Rachida Djebaili; Samir Kenouche; Ismail Daoud; Nadjib Melkemi; Ahlem Belkadi; Fouzia Mesli

doi:10.1007/s11224-022-02029-4

Investigation of [³H]diazepam derivatives as allosteric modulators of GABAA receptor α₁β₂γ₂ subtypes: combination of molecular docking/dynamic simulations, pharmacokinetics/drug-likeness prediction, and QSAR analysis

Struct Chem. 2023;34(3):791-823. doi: 10.1007/s11224-022-02029-4. Epub 2022 Aug 11.

Authors

Rachida Djebaili¹, Samir Kenouche², Ismail Daoud^{3

4}, Nadjib Melkemi¹, Ahlem Belkadi¹, Fouzia Mesli³

Affiliations

¹ 07000 Biskra, Algeria Group of Computational and Pharmaceutical Chemistry, LMCE Laboratory, University of Mohamed Khider.
² 07000 Biskra, Algeria Group of Modeling of Chemical Systems Using Quantum Calculations, Applied Chemistry Laboratory (LCA), University of Mohamed Khider.
³ Laboratory of Natural and Bioactive Substances, LASNABIO, University of Abou-BakrBelkaid, Tlemcen, Algeria.
⁴ BP 145 RP, 07000 Biskra, Algeria Present address: Department of Matter Sciences, University of Mohamed Khider Biskra.

Abstract

In this paper, a data set of [³H] diazepam derivatives was analyzed using various computational methods: molecular docking/dynamic simulations, and QSAR analysis. The main aims of these studies are to understand the binding mechanisms by which benzodiazepines allosterically modulate GABA_A receptor α₁β₂γ₂ subtypes, from inducing neuronal inhibition at lower doses to the anesthetic effect at higher doses, and also, to define the structural requirements that contribute to improving the response of GABA_A/α₁β₂γ₂ receptor to benzodiazepine drugs. The results of the molecular docking study allowed selecting Ro12-6377 and proflazepam as the best modulators for the four binding sites simultaneously. Subsequently, the stability of the selected complexes was investigated by performing molecular dynamics simulation. The latter confirmed the features of both modulators to exert direct effects on the chloride-channel lining residues. Pharmacokinetics and drug-likeness profile were assessed through in silico tool. Furthermore, a QSAR analysis was conducted using an improved vemolecular dynamics simulations proposed byrsion of PLS regression. The goodness of fit and the predictive power of the resulting PLS model were estimated according to internal and external validation parameters: R² = 0.632, R²_adj = 0.584, F = 12.806; p-value = 6.2050e - 07, Q²_loo = 0.639, and Q²_F3 = 0.813. Clearly, the obtained results ensure the predictive ability of the developed QSAR model for the design of new high-potency benzodiazepine drugs.

Supplementary information: The online version contains supplementary material available at 10.1007/s11224-022-02029-4.

Keywords: Benzodiazepine; Chloride channel; Extracellular domain; GABAA receptor; TM2 helix; Transmembrane domain.

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.