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

Abstract

In this paper, a data set of [ 3 H] 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 α 1 β 2 γ 2 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 /α 1 β 2 γ 2 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: R 2 = 0.632, R 2 adj = 0.584, F = 12.806; p- value = 6.2050e − 07, Q 2 loo = 0.639, and Q 2 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.

In vitro and in silico studies of prenylated phenylpropanoids of green propolis and their derivatives against cariogenic bacteria

“…Finally, the 3LE0-Compound 8, 4N82-Compound 8, and 3AIC-Compound 8 complexes retain their stabilities in the last intervals (between 800 and 1500 ps, between 400 and 1500 ps, and between 900-1500 ps, respectively) (Figure 5a, b, and c). On the other hand, all the studied complexes exhibit higher stability, confirmed by MD simulations, because they maintained almost the same types of interactions compared to the molecular docking studies, which was also confirmed by the stability of the potential energy as a function of time (Figure 5a, b, and c), as reported in recent papers [73,74].…”

Quercetin Antagonizes the Sedative Effects of Linalool, Possibly through the GABAergic Interaction Pathway

“…On the other hand, the major GABA A receptor isoform is made up of two α-subtypes, two β-subtypes, and one γ-subtype, or one δ-subtype. In the adult brain, 90% of GABA A receptors are γ-containing receptors, which are mostly distributed in synaptic locations [ 16 ]. However, it is generally accepted that the primary mature isoform consists of α1, β2, and γ2 subunits, which are positioned as γ2β2α1β2α1 counterclockwise around a central pore when observed from the outside of the cell [ 17 ].…”