Abstract
The ionotropic GABAA receptor (GABAAR) has been proven to be an important target of atypical antipsychotics. A novel series of imidazo [1,2-a]-pyridine derivatives, as selective positive allosteric modulators (PAMs) of α1-containing GABAARs with potent antipsychotic activities, have been reported recently. To better clarify the pharmacological essentiality of these PAMs and explore novel antipsychotics hits, three-dimensional quantitative structure–activity relationships (3D-QSAR), molecular docking, pharmacophore modeling, and molecular dynamics (MD) were performed on 33 imidazo [1,2-a]-pyridines. The constructed 3D-QSAR models exhibited good predictive abilities. The dockings results and MD simulations demonstrated that hydrogen bonds, π–π stackings, and hydrophobic interactions play essential roles in the binding of these novel PAMs in the GABAAR binding pocket. Four hit compounds (DS01–04) were then screened out by the combination of the constructed models and computations, including the pharmacophore model, Topomer Search, molecular dockings, ADME/T predictions, and MD simulations. The compounds DS03 and DS04, with higher docking scores and better predicted activities, were also found to be relatively stable in the binding pocket by MD simulations. These results might provide a significant theoretical direction or information for the rational design and development of novel α1-GABAAR PAMs with antipsychotic activities.
Highlights
Schizophrenia, a persistent and chronic psychiatric disorder, affects about 1% of the worldwide population [1,2]
The 3D-QSAR models were constructed based on 33 imidazo [1,2-a]-pyridines, to visually understand the effect of diverse substitutions on the activity of these GABAA receptor (GABAAR) positive allosteric modulators (PAMs)
The molecular docking studies revealed the interaction patterns of these PAMs in the BZD pocket, indicating that these imidazo [1,2-a]pyridines could form key hydrogen bonds with the residues Ser205 (α1) and Ser206 (α1), and could form hydrophobic or π–π stacking interactions with the residues Phe100 (α1), His102 (α1), Tyr160 (α1), Val203 (α1), Tyr210 (α1), and Phe77 (γ2). These interactions might be essential for the bindings or activities of these GABAAR PAMs
Summary
Schizophrenia, a persistent and chronic psychiatric disorder, affects about 1% of the worldwide population [1,2]. Postmortem studies indicated lower brain levels of the GABA neurotransmitter in schizophrenia patients [20]. Hofman’s research showed a lower level of mRNA of the α1 subtype of GABAAR in the prefrontal cortices of schizophrenia patients [21]. Pharmacological studies have found that zolpidem, as a selective α1-GABAAR-positive allosteric modulator (PAM), displayed antipsychotic-like effects in a rat at low dose level, comparable to the second-generation antipsychotic risperidone [23,24,25]. To find novel α1‐GABAAR PAMs, virtual screening was performed based on the best pharmacophore model combined with Topomer Search, molecular dockings, and. To find novel α1-GABAAR PAMs, virtual screening was performed based on the best pharmacophore model combined with Topomer Search, molecular dockings, and ADME/T predictions.
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