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Demystifying the Molecular Basis of Pyrazoloquinolinones Recognition at the Extracellular ?1+/?3- Interface of the GABAA Receptor by Molecular Modeling.

ABSTRACT: GABAA receptors are pentameric ligand-gated ion channels that serve as major inhibitory neurotransmitter receptors in the mammalian brain and the target of numerous clinically relevant drugs interacting with different ligand binding sites. Here, we report an in silico approach to investigate the binding of pyrazoloquinolinones (PQs) that mediate allosteric effects through the extracellular ?+/?- interface of GABAA receptors. First, we docked a potent prototype of PQs into the ?1+/?3- site of a homology model of the human ?1?3?2 subtype of the GABAA receptor. Next, for each docking pose, we computationally derived protein-ligand complexes for 18 PQ analogs with known experimental potency. Subsequently, binding energy was calculated for all complexes using the molecular mechanics-generalized Born surface area method. Finally, docking poses were quantitatively assessed in the light of experimental data to derive a binding hypothesis. Collectively, the results indicate that PQs at the ?1+/?3- site likely exhibit a common binding mode that can be characterized by a hydrogen bond interaction with ?3Q64 and hydrophobic interactions involving residues ?1F99, ?3Y62, ?3M115, ?1Y159, and ?1Y209. Importantly, our results are in good agreement with the recently resolved cryo-Electron Microscopy structures of the human ?1?3?2 and ?1?2?2 subtypes of GABAA receptors.

SUBMITTER: Singh N

PROVIDER: S-EPMC7518038 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Demystifying the Molecular Basis of Pyrazoloquinolinones Recognition at the Extracellular α1+/β3- Interface of the GABAA Receptor by Molecular Modeling.

Singh Natesh N Villoutreix Bruno O BO

Frontiers in pharmacology 20200911

GABAA receptors are pentameric ligand-gated ion channels that serve as major inhibitory neurotransmitter receptors in the mammalian brain and the target of numerous clinically relevant drugs interacting with different ligand binding sites. Here, we report an in silico approach to investigate the binding of pyrazoloquinolinones (PQs) that mediate allosteric effects through the extracellular α+/β- interface of GABAA receptors. First, we docked a potent prototype of PQs into t ...[more]

PMID: 33041802

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Project description:BackgroundDisruption of normal brain development is implicated in numerous psychiatric disorders with neurodevelopmental origins, including autism spectrum disorder (ASD). Widespread abnormalities in brain structure and functions caused by dysregulations of neurodevelopmental processes has been recently shown to exert adverse effects across generations. An imbalance between excitatory/inhibitory (E/I) transmission is the putative hypothesis of ASD pathogenesis, supporting by the specific implications of inhibitory γ-aminobutyric acid (GABA)ergic system in autistic individuals and animal models of ASD. However, the contribution of GABAergic system in the neuropathophysiology across generations of ASD is still unknown. Here, we uncover profound alterations in the expression and function of GABAA receptors (GABAARs) in the amygdala across generations of the VPA-induced animal model of ASD.MethodsThe F2 generation was produced by mating an F1 VPA-induced male offspring with naïve females after a single injection of VPA on embryonic day (E12.5) in F0. Autism-like behaviors were assessed by animal behavior tests. Expression and functional properties of GABAARs and related proteins were examined by using western blotting and electrophysiological techniques.ResultsSocial deficit, repetitive behavior, and emotional comorbidities were demonstrated across two generations of the VPA-induced offspring. Decreased synaptic GABAAR and gephyrin levels, and inhibitory transmission were found in the amygdala from two generations of the VPA-induced offspring with greater reductions in the F2 generation. Weaker association of gephyrin with GABAAR was shown in the F2 generation than the F1 generation. Moreover, dysregulated NMDA-induced enhancements of gephyrin and GABAAR at the synapse in the VPA-induced offspring was worsened in the F2 generation than the F1 generation. Elevated glutamatergic modifications were additionally shown across generations of the VPA-induced offspring without generation difference.ConclusionsTaken together, these findings revealed the E/I synaptic abnormalities in the amygdala from two generations of the VPA-induced offspring with GABAergic deteriorations in the F2 generation, suggesting a potential therapeutic role of the GABAergic system to generational pathophysiology of ASD.

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Demystifying the Molecular Basis of Pyrazoloquinolinones Recognition at the Extracellular ?1+/?3- Interface of the GABAA Receptor by Molecular Modeling.

Publications

Demystifying the Molecular Basis of Pyrazoloquinolinones Recognition at the Extracellular α1+/β3- Interface of the GABA<sub>A</sub> Receptor by Molecular Modeling.

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Demystifying the Molecular Basis of Pyrazoloquinolinones Recognition at the Extracellular ?1+/?3- Interface of the GABAA Receptor by Molecular Modeling.

Publications

Demystifying the Molecular Basis of Pyrazoloquinolinones Recognition at the Extracellular α1+/β3- Interface of the GABA&lt;sub&gt;A&lt;/sub&gt; Receptor by Molecular Modeling.

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OmicsDI is part of the ELIXIR infrastructure

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Demystifying the Molecular Basis of Pyrazoloquinolinones Recognition at the Extracellular α1+/β3- Interface of the GABA<sub>A</sub> Receptor by Molecular Modeling.