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Receptor-based pharmacophore modeling, virtual screening, and molecular docking studies for the discovery of novel GSK-3β inhibitors.
J Mol Model. 2019 May 25; 25(6):171.JM

Abstract

Considering the emerging importance of glycogen synthase kinase 3 beta (GSK-3β) inhibitors in treatment of Alzheimer's disease, multi-protein structure receptor-based pharmacophore modeling was adopted to generate a 3D pharmacophore model for (GSK-3β) inhibitors. The generated 3D pharmacophore was then validated using a test set of 1235 compounds. The ZINCPharmer web tool was used to virtually screen the public ZINC database using the generated 3D pharmacophore. A set of 12,251 hits was produced and then filtered according to their lead-like properties, predicted central nervous system (CNS) activity, and Pan-assay interference compounds (PAINS) fragments to 630 compounds. Scaffold Hunter was then used to cluster the filtered compounds according to their chemical structure framework. From the different clusters, 123 compounds were selected to cover the whole chemical space of the obtained hits. The SwissADME online tool was then used to filter out the compounds with undesirable pharmacokinetic properties giving a set of 91 compounds with promising predicted pharmacodynamic and pharmacokinetic properties. To confirm their binding capability to the GSK-3β binding site, molecular docking simulations were performed for the final 91 compounds in the GSK-3β binding site. Twenty-five compounds showed acceptable binding poses that bind to the key amino acids in the binding site Asp133 and Val135 with good binding scores. The quinolin-2-one derivative ZINC67773573 was found to be a promising lead for designing new GSK-3β inhibitors for Alzheimer's disease treatment. Graphical abstract A 3D pharmacophore model for the discovery of novel (GSK-3β) inhibitors.

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Publisher Full Text (DOI)

Authors+Show Affiliations

El Kerdawy AM
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt. Ahmed.elkerdawy@cu.edu.eg. Molecular Modeling Unit, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt. Ahmed.elkerdawy@cu.edu.eg. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, Newgiza, km 22 Cairo-Alexandria Desert Road, Cairo, Egypt. Ahmed.elkerdawy@cu.edu.eg.
Osman AA
Bachelor of Pharmacy Program, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt.
Zaater MA
Research and Development Unit, Majecules LLC, 124 Othman Ibn Affan, Al Matar, P.O. Box 11361, Cairo, Egypt.

MeSH

Alzheimer DiseaseBinding SitesCrystallography, X-RayDrug DesignEnzyme InhibitorsGlycogen Synthase Kinase 3 betaMolecular ConformationMolecular Docking SimulationMolecular Dynamics SimulationMolecular StructureProtein Binding

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31129879

Citation

El Kerdawy, Ahmed M., et al. "Receptor-based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for the Discovery of Novel GSK-3β Inhibitors." Journal of Molecular Modeling, vol. 25, no. 6, 2019, p. 171.
El Kerdawy AM, Osman AA, Zaater MA. Receptor-based pharmacophore modeling, virtual screening, and molecular docking studies for the discovery of novel GSK-3β inhibitors. J Mol Model. 2019;25(6):171.
El Kerdawy, A. M., Osman, A. A., & Zaater, M. A. (2019). Receptor-based pharmacophore modeling, virtual screening, and molecular docking studies for the discovery of novel GSK-3β inhibitors. Journal of Molecular Modeling, 25(6), 171. https://doi.org/10.1007/s00894-019-4032-5
El Kerdawy AM, Osman AA, Zaater MA. Receptor-based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies for the Discovery of Novel GSK-3β Inhibitors. J Mol Model. 2019 May 25;25(6):171. PubMed PMID: 31129879.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Receptor-based pharmacophore modeling, virtual screening, and molecular docking studies for the discovery of novel GSK-3β inhibitors. AU - El Kerdawy,Ahmed M, AU - Osman,Alaa A, AU - Zaater,Marwa A, Y1 - 2019/05/25/ PY - 2019/02/03/received PY - 2019/04/07/accepted PY - 2019/5/27/entrez PY - 2019/5/28/pubmed PY - 2019/11/21/medline KW - Alzheimer’s disease KW - GSK-3β KW - Molecular docking KW - Pharmacophore modeling KW - Tau protein aggregation KW - Virtual screening SP - 171 EP - 171 JF - Journal of molecular modeling JO - J Mol Model VL - 25 IS - 6 N2 - Considering the emerging importance of glycogen synthase kinase 3 beta (GSK-3β) inhibitors in treatment of Alzheimer's disease, multi-protein structure receptor-based pharmacophore modeling was adopted to generate a 3D pharmacophore model for (GSK-3β) inhibitors. The generated 3D pharmacophore was then validated using a test set of 1235 compounds. The ZINCPharmer web tool was used to virtually screen the public ZINC database using the generated 3D pharmacophore. A set of 12,251 hits was produced and then filtered according to their lead-like properties, predicted central nervous system (CNS) activity, and Pan-assay interference compounds (PAINS) fragments to 630 compounds. Scaffold Hunter was then used to cluster the filtered compounds according to their chemical structure framework. From the different clusters, 123 compounds were selected to cover the whole chemical space of the obtained hits. The SwissADME online tool was then used to filter out the compounds with undesirable pharmacokinetic properties giving a set of 91 compounds with promising predicted pharmacodynamic and pharmacokinetic properties. To confirm their binding capability to the GSK-3β binding site, molecular docking simulations were performed for the final 91 compounds in the GSK-3β binding site. Twenty-five compounds showed acceptable binding poses that bind to the key amino acids in the binding site Asp133 and Val135 with good binding scores. The quinolin-2-one derivative ZINC67773573 was found to be a promising lead for designing new GSK-3β inhibitors for Alzheimer's disease treatment. Graphical abstract A 3D pharmacophore model for the discovery of novel (GSK-3β) inhibitors. SN - 0948-5023 UR - https://www.unboundmedicine.com/medline/citation/31129879/Receptor_based_pharmacophore_modeling_virtual_screening_and_molecular_docking_studies_for_the_discovery_of_novel_GSK_3β_inhibitors_ DB - PRIME DP - Unbound Medicine ER -