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Molecular docking analysis of ?2-containing GABAA receptors with benzimidazoles derivatives.

ABSTRACT: It is of interest to study the binding capacity of "3-[2-(2-Amino-1H-benzo[d]imidazol-1-yl)ethyl]-1,3-oxazolidin-2-one" (OXB2) with the active site of gamma-aminobutyric acid (GABA) located in the GABA type A receptor (GABAAR) in comparison with different GABAA subtypes. Optimal binding features were observed with the ?2?2?2 isoform (-8 kcal/mol). This is similar (-7.3 and -7.2 kcal/mol, respectively) for subtypes (?3?2?2 and ?1?2?2). This implies that OXB2 binds preferentially to subtypes associated with anxiety (?2- and/or ?3-containing receptors) linked molecules than with the subtype associated with sedation (?1-containing receptors). It is further noted that molecular dynamics simulation data of the complex (OXB2-GABAAR) shows adequate structural stability in aqueous environment. Moreover, relevant ADMET data is found adequate for further consideration.

SUBMITTER: Bouayyadi A

PROVIDER: S-EPMC7649024 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Molecular docking analysis of α2-containing GABAA receptors with benzimidazoles derivatives.

Bouayyadi Abdellatif A Aliani Aissam El AE Kasmi Yassine Y Moussaif Ahmed A Abbadi Najia El NE Mesfioui Abdelhalim A Essassi El Mokhtar EM Mzibri Mohammed El ME

Bioinformation 20200831 8

It is of interest to study the binding capacity of "3-[2-(2-Amino-1H-benzo[d]imidazol-1-yl)ethyl]-1,3-oxazolidin-2-one" (OXB2) with the active site of gamma-aminobutyric acid (GABA) located in the GABA type A receptor (GABAAR) in comparison with different GABAA subtypes. Optimal binding features were observed with the α2β2γ2 isoform (-8 kcal/mol). This is similar (-7.3 and -7.2 kcal/mol, respectively) for subtypes (α3β2γ2 and α1β2γ2). This implies that OXB2 binds preferentially to subtypes assoc ...[more]

PMID: 33214749

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Project description:GABAA receptors are pentameric GABA-gated chloride channels. The existence of 19 different subunits (six α, three β, three γ, δ, ε, θ, π, and three ρ) in mammalian systems gives rise to an enormous theoretical diversity of GABAA receptor subtypes with distinct subunit composition and unique pharmacological properties. These receptors are already now the drug targets of several clinically used compounds, such as benzodiazepines, anesthetics, and many more. There is a constant quest to identify novel molecules and possible future drug targets: Currently, α6-containing GABAA receptors are being discussed in the context of treating sensorimotor gating deficits in neuropsychiatric disorders, such as tic disorders and schizophrenia. Therefore, we aim to learn more about α6-containing GABAA receptors. They are mostly expressed in the cerebellar granule cell layer, where they form the following subtypes: α6βxγ2, α1α6βxγ2, α6βxδ, and α1α6βxδ. In former studies, α1α6βxγ2-containing GABAA receptors were considered a single receptor population. In the current study, we investigate the possibility, that this population can consist of two subgroups with alternative arrangements depending if α1 neighbors γ2 (forming a "diazepam-sensitive" receptor), or if α6 neighbors γ2 (forming a "diazepam-insensitive" receptor) and aimed to prove the existence of both subtypes in native tissue. We performed immunoprecipitation experiments on rat cerebellar lysates using α1- or α6 subunit-specific antibodies followed by radioligand binding assays with either 3H-flunitrazepam or 3H-Ro 15-4513. Indeed, we were able to prove the existence of two distinct populations of α1α6-containing GABAA-receptors and could quantify the different receptor populations: α1βxγ2 receptors constitute approximately 60% of all γ2-containing receptors in the rat cerebellum, α6βxγ2 about 20%, and both isoforms of α1α6βxγ2 9-15% each. The simple classification of GABAA-receptors into αx-containing subtypes seems not to reflect the complexity of nature; those receptors are more diverse than previously thought.

Dataset Information

Molecular docking analysis of ?2-containing GABAA receptors with benzimidazoles derivatives.

Publications

Molecular docking analysis of α2-containing GABAA receptors with benzimidazoles derivatives.

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