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Novel hybrid virtual screening protocol based on pharmacophore and molecular docking for discovery of GSK-3β inhibitors.
Chem Biol Drug Des. 2023 02; 101(2):326-339.CB

Abstract

GSK-3β is a member of the GSKs subfamily and plays a major role in the regulation of transcriptional elongation, which has attracted widespread attention as a therapeutic target for AD. In this study, by combining pharmacophore-based virtual screening and kinase inhibition assays, we have successfully identified four small molecules that inhibit GSK-3β activity at micromolar potency. These hit compounds showed drug-like properties according to Lipinski's rule of five and ADMET. An inter-complex interaction study showed that all hit compounds adapted well to the ATP pocket of the GSK-3β protein. Among them, hits 2 and 4 displayed considerable inhibitory activities with IC50 value of 0.74 ± 0.04 μM and 2.32 ± 0.84 μM respectively. Overall, the discovered GSK-3β inhibitors act as new chemical leads to develop improved inhibitors that block the interaction of GSK-3β, and the hybrid virtual screening strategy designed in this study provides an important reference for design and synthesis novel selective GSK-3β inhibitors.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Liu X
Department of Pharmacy, Guangdong Provincial People's Hospital Zhuhai Hospital (Zhuhai Golden Bay Center Hospital), Zhuhai, China.
Yu J
Department of Pharmacy, Guangdong Provincial People's Hospital Zhuhai Hospital (Zhuhai Golden Bay Center Hospital), Zhuhai, China.
Luo Y
Department of Pharmacy, Guangdong Provincial People's Hospital Zhuhai Hospital (Zhuhai Golden Bay Center Hospital), Zhuhai, China.
Dong H
Department of Cardiology, Vascular Center, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary, Guangzhou, China. Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangzhou, China. Guangdong Academy of Medical Sciences, Guangzhou, China.

MeSH

Molecular Docking SimulationGlycogen Synthase Kinase 3 betaPharmacophoreProtein BindingProtein Kinase Inhibitors

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

35762873

Citation

Liu, Xiaochang, et al. "Novel Hybrid Virtual Screening Protocol Based On Pharmacophore and Molecular Docking for Discovery of GSK-3β Inhibitors." Chemical Biology & Drug Design, vol. 101, no. 2, 2023, pp. 326-339.
Liu X, Yu J, Luo Y, et al. Novel hybrid virtual screening protocol based on pharmacophore and molecular docking for discovery of GSK-3β inhibitors. Chem Biol Drug Des. 2023;101(2):326-339.
Liu, X., Yu, J., Luo, Y., & Dong, H. (2023). Novel hybrid virtual screening protocol based on pharmacophore and molecular docking for discovery of GSK-3β inhibitors. Chemical Biology & Drug Design, 101(2), 326-339. https://doi.org/10.1111/cbdd.14111
Liu X, et al. Novel Hybrid Virtual Screening Protocol Based On Pharmacophore and Molecular Docking for Discovery of GSK-3β Inhibitors. Chem Biol Drug Des. 2023;101(2):326-339. PubMed PMID: 35762873.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel hybrid virtual screening protocol based on pharmacophore and molecular docking for discovery of GSK-3β inhibitors. AU - Liu,Xiaochang, AU - Yu,Jiaxue, AU - Luo,Yongyan, AU - Dong,Haojian, Y1 - 2022/12/05/ PY - 2022/06/21/revised PY - 2022/01/05/received PY - 2022/06/26/accepted PY - 2022/6/29/pubmed PY - 2023/1/14/medline PY - 2022/6/28/entrez KW - GSK-3β KW - hits 2 and 4 KW - kinase inhibition KW - pharmacophore-based virtual screening SP - 326 EP - 339 JF - Chemical biology & drug design JO - Chem Biol Drug Des VL - 101 IS - 2 N2 - GSK-3β is a member of the GSKs subfamily and plays a major role in the regulation of transcriptional elongation, which has attracted widespread attention as a therapeutic target for AD. In this study, by combining pharmacophore-based virtual screening and kinase inhibition assays, we have successfully identified four small molecules that inhibit GSK-3β activity at micromolar potency. These hit compounds showed drug-like properties according to Lipinski's rule of five and ADMET. An inter-complex interaction study showed that all hit compounds adapted well to the ATP pocket of the GSK-3β protein. Among them, hits 2 and 4 displayed considerable inhibitory activities with IC50 value of 0.74 ± 0.04 μM and 2.32 ± 0.84 μM respectively. Overall, the discovered GSK-3β inhibitors act as new chemical leads to develop improved inhibitors that block the interaction of GSK-3β, and the hybrid virtual screening strategy designed in this study provides an important reference for design and synthesis novel selective GSK-3β inhibitors. SN - 1747-0285 UR - https://www.unboundmedicine.com/medline/citation/35762873/Novel_hybrid_virtual_screening_protocol_based_on_pharmacophore_and_molecular_docking_for_discovery_of_GSK_3β_inhibitors_ DB - PRIME DP - Unbound Medicine ER -