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Identification of Novel Inhibitors Targeting SGK1 via Ensemble-Based Virtual Screening Method, Biological Evaluation and Molecular Dynamics Simulation

Serum and glucocorticoid-regulated kinase 1 (SGK1), as a serine threonine protein kinase of the AGC family, regulates different enzymes, transcription factors, ion channels, transporters, and cell proliferation and apoptosis. Inhibition of SGK1 is considered as a valuable approach for the treatment...

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Autores principales: Zhang, Hui, Shen, Chen, Zhang, Hong-Rui, Qi, Hua-Zhao, Hu, Mei-Ling, Luo, Qing-Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9369041/
https://www.ncbi.nlm.nih.gov/pubmed/35955763
http://dx.doi.org/10.3390/ijms23158635
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author Zhang, Hui
Shen, Chen
Zhang, Hong-Rui
Qi, Hua-Zhao
Hu, Mei-Ling
Luo, Qing-Qing
author_facet Zhang, Hui
Shen, Chen
Zhang, Hong-Rui
Qi, Hua-Zhao
Hu, Mei-Ling
Luo, Qing-Qing
author_sort Zhang, Hui
collection PubMed
description Serum and glucocorticoid-regulated kinase 1 (SGK1), as a serine threonine protein kinase of the AGC family, regulates different enzymes, transcription factors, ion channels, transporters, and cell proliferation and apoptosis. Inhibition of SGK1 is considered as a valuable approach for the treatment of various metabolic diseases. In this investigation, virtual screening methods, including pharmacophore models, Bayesian classifiers, and molecular docking, were combined to discover novel inhibitors of SGK1 from the database with 29,158 compounds. Then, the screened compounds were subjected to ADME/T, PAINS and drug-likeness analysis. Finally, 28 compounds with potential inhibition activity against SGK1 were selected for biological evaluation. The kinase inhibition activity test revealed that among these 28 hits, hit15 exhibited the highest inhibition activity against SGK1, which gave 44.79% inhibition rate at the concentration of 10 µM. In order to further investigate the interaction mechanism of hit15 and SGK1 at simulated physiological conditions, a molecular dynamics simulation was performed. The molecular dynamics simulation demonstrated that hit15 could bind to the active site of SGK1 and form stable interactions with key residues, such as Tyr178, ILE179, and VAL112. The binding free energy of the SGK1-hit15 was −48.90 kJ mol(−1). Therefore, the identified hit15 with novel scaffold may be a promising lead compound for development of new SGK1 inhibitors for various diseases treatment.
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spelling pubmed-93690412022-08-12 Identification of Novel Inhibitors Targeting SGK1 via Ensemble-Based Virtual Screening Method, Biological Evaluation and Molecular Dynamics Simulation Zhang, Hui Shen, Chen Zhang, Hong-Rui Qi, Hua-Zhao Hu, Mei-Ling Luo, Qing-Qing Int J Mol Sci Article Serum and glucocorticoid-regulated kinase 1 (SGK1), as a serine threonine protein kinase of the AGC family, regulates different enzymes, transcription factors, ion channels, transporters, and cell proliferation and apoptosis. Inhibition of SGK1 is considered as a valuable approach for the treatment of various metabolic diseases. In this investigation, virtual screening methods, including pharmacophore models, Bayesian classifiers, and molecular docking, were combined to discover novel inhibitors of SGK1 from the database with 29,158 compounds. Then, the screened compounds were subjected to ADME/T, PAINS and drug-likeness analysis. Finally, 28 compounds with potential inhibition activity against SGK1 were selected for biological evaluation. The kinase inhibition activity test revealed that among these 28 hits, hit15 exhibited the highest inhibition activity against SGK1, which gave 44.79% inhibition rate at the concentration of 10 µM. In order to further investigate the interaction mechanism of hit15 and SGK1 at simulated physiological conditions, a molecular dynamics simulation was performed. The molecular dynamics simulation demonstrated that hit15 could bind to the active site of SGK1 and form stable interactions with key residues, such as Tyr178, ILE179, and VAL112. The binding free energy of the SGK1-hit15 was −48.90 kJ mol(−1). Therefore, the identified hit15 with novel scaffold may be a promising lead compound for development of new SGK1 inhibitors for various diseases treatment. MDPI 2022-08-03 /pmc/articles/PMC9369041/ /pubmed/35955763 http://dx.doi.org/10.3390/ijms23158635 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Hui
Shen, Chen
Zhang, Hong-Rui
Qi, Hua-Zhao
Hu, Mei-Ling
Luo, Qing-Qing
Identification of Novel Inhibitors Targeting SGK1 via Ensemble-Based Virtual Screening Method, Biological Evaluation and Molecular Dynamics Simulation
title Identification of Novel Inhibitors Targeting SGK1 via Ensemble-Based Virtual Screening Method, Biological Evaluation and Molecular Dynamics Simulation
title_full Identification of Novel Inhibitors Targeting SGK1 via Ensemble-Based Virtual Screening Method, Biological Evaluation and Molecular Dynamics Simulation
title_fullStr Identification of Novel Inhibitors Targeting SGK1 via Ensemble-Based Virtual Screening Method, Biological Evaluation and Molecular Dynamics Simulation
title_full_unstemmed Identification of Novel Inhibitors Targeting SGK1 via Ensemble-Based Virtual Screening Method, Biological Evaluation and Molecular Dynamics Simulation
title_short Identification of Novel Inhibitors Targeting SGK1 via Ensemble-Based Virtual Screening Method, Biological Evaluation and Molecular Dynamics Simulation
title_sort identification of novel inhibitors targeting sgk1 via ensemble-based virtual screening method, biological evaluation and molecular dynamics simulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9369041/
https://www.ncbi.nlm.nih.gov/pubmed/35955763
http://dx.doi.org/10.3390/ijms23158635
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