期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 17, 页码 -出版社
MDPI
DOI: 10.3390/ijms22179645
关键词
GABA(A) receptor; positive allosteric modulators; 3D-QSAR; docking; pharmacophore; virtual screening
资金
- National Natural Science Foundation of China [22177090, 21807082]
- Outstanding Young and Middle-aged Scientific Innovation Team of Colleges and Universities of Hubei Province: Biomass chemical technologies and materials [T201908]
- Special Projects of the Central Government in Guidance of Local Science and Technology Development in Hubei Province [2020ZYYD040]
- Key Research and Development Project of Hubei Province [2020BAB073]
The study investigated a novel series of imidazo[1,2-a]-pyridine derivatives for their binding modes in the GABA(A) receptor binding pocket using various methods. The results provide important information for the development of novel drugs with antipsychotic activities.
The ionotropic GABA(A) receptor (GABA(A)R) 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 alpha 1-containing GABA(A)Rs 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, pi-pi stackings, and hydrophobic interactions play essential roles in the binding of these novel PAMs in the GABA(A)R 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 alpha 1-GABA(A)R PAMs with antipsychotic activities.
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