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3D-QSAR Studies, Molecular Docking, Molecular Dynamic Simulation, and ADMET Proprieties of Novel Pteridinone Derivatives as PLK1 Inhibitors for the Treatment of Prostate Cancer
Overexpression of polo-like kinase 1 (PLK1) has been found in many different types of cancers. With its essential role in cell proliferation, PLK1 has been determined to be a broad-spectrum anti-cancer target. In this study, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations were ap...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865323/ https://www.ncbi.nlm.nih.gov/pubmed/36676076 http://dx.doi.org/10.3390/life13010127 |
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author | Er-rajy, Mohammed El fadili, Mohamed Imtara, Hamada Saeed, Aamir Ur Rehman, Abid Zarougui, Sara Abdullah, Shaef A. Alahdab, Ahmad Parvez, Mohammad Khalid Elhallaoui, Menana |
author_facet | Er-rajy, Mohammed El fadili, Mohamed Imtara, Hamada Saeed, Aamir Ur Rehman, Abid Zarougui, Sara Abdullah, Shaef A. Alahdab, Ahmad Parvez, Mohammad Khalid Elhallaoui, Menana |
author_sort | Er-rajy, Mohammed |
collection | PubMed |
description | Overexpression of polo-like kinase 1 (PLK1) has been found in many different types of cancers. With its essential role in cell proliferation, PLK1 has been determined to be a broad-spectrum anti-cancer target. In this study, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations were applied on a series of novel pteridinone derivatives as PLK1 inhibitors to discover anti-cancer drug candidates. In this work, three models—CoMFA (Q² = 0.67, R² = 0.992), CoMSIA/SHE (Q² = 0.69, R² = 0.974), and CoMSIA/SEAH (Q² = 0.66, R² = 0.975)—of pteridinone derivatives were established. The three models that were established gave [Formula: see text] = 0.683, [Formula: see text] = 0.758, and [Formula: see text] = 0.767, respectively. Thus, the predictive abilities of the three proposed models were successfully evaluated. The relations between the different champs and activities were well-demonstrated by the contour chart of the CoMFA and CoMSIA/SEAH models. The results of molecular docking indicated that residues R136, R57, Y133, L69, L82, and Y139 were the active sites of the PLK1 protein (PDB code: 2RKU), in which the more active ligands can inhibit the enzyme of PLK1. The results of the molecular dynamic MD simulation diagram were obtained to reinforce the previous molecular docking results, which showed that both inhibitors remained stable in the active sites of the PLK1 protein (PDB code: 2RKU) for 50 ns. Finally, a check of the ADME-Tox properties of the two most active molecules showed that molecular N° 28 could represent a good drug candidate for the therapy of prostate cancer diseases. |
format | Online Article Text |
id | pubmed-9865323 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-98653232023-01-22 3D-QSAR Studies, Molecular Docking, Molecular Dynamic Simulation, and ADMET Proprieties of Novel Pteridinone Derivatives as PLK1 Inhibitors for the Treatment of Prostate Cancer Er-rajy, Mohammed El fadili, Mohamed Imtara, Hamada Saeed, Aamir Ur Rehman, Abid Zarougui, Sara Abdullah, Shaef A. Alahdab, Ahmad Parvez, Mohammad Khalid Elhallaoui, Menana Life (Basel) Article Overexpression of polo-like kinase 1 (PLK1) has been found in many different types of cancers. With its essential role in cell proliferation, PLK1 has been determined to be a broad-spectrum anti-cancer target. In this study, 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations were applied on a series of novel pteridinone derivatives as PLK1 inhibitors to discover anti-cancer drug candidates. In this work, three models—CoMFA (Q² = 0.67, R² = 0.992), CoMSIA/SHE (Q² = 0.69, R² = 0.974), and CoMSIA/SEAH (Q² = 0.66, R² = 0.975)—of pteridinone derivatives were established. The three models that were established gave [Formula: see text] = 0.683, [Formula: see text] = 0.758, and [Formula: see text] = 0.767, respectively. Thus, the predictive abilities of the three proposed models were successfully evaluated. The relations between the different champs and activities were well-demonstrated by the contour chart of the CoMFA and CoMSIA/SEAH models. The results of molecular docking indicated that residues R136, R57, Y133, L69, L82, and Y139 were the active sites of the PLK1 protein (PDB code: 2RKU), in which the more active ligands can inhibit the enzyme of PLK1. The results of the molecular dynamic MD simulation diagram were obtained to reinforce the previous molecular docking results, which showed that both inhibitors remained stable in the active sites of the PLK1 protein (PDB code: 2RKU) for 50 ns. Finally, a check of the ADME-Tox properties of the two most active molecules showed that molecular N° 28 could represent a good drug candidate for the therapy of prostate cancer diseases. MDPI 2023-01-02 /pmc/articles/PMC9865323/ /pubmed/36676076 http://dx.doi.org/10.3390/life13010127 Text en © 2023 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 Er-rajy, Mohammed El fadili, Mohamed Imtara, Hamada Saeed, Aamir Ur Rehman, Abid Zarougui, Sara Abdullah, Shaef A. Alahdab, Ahmad Parvez, Mohammad Khalid Elhallaoui, Menana 3D-QSAR Studies, Molecular Docking, Molecular Dynamic Simulation, and ADMET Proprieties of Novel Pteridinone Derivatives as PLK1 Inhibitors for the Treatment of Prostate Cancer |
title | 3D-QSAR Studies, Molecular Docking, Molecular Dynamic Simulation, and ADMET Proprieties of Novel Pteridinone Derivatives as PLK1 Inhibitors for the Treatment of Prostate Cancer |
title_full | 3D-QSAR Studies, Molecular Docking, Molecular Dynamic Simulation, and ADMET Proprieties of Novel Pteridinone Derivatives as PLK1 Inhibitors for the Treatment of Prostate Cancer |
title_fullStr | 3D-QSAR Studies, Molecular Docking, Molecular Dynamic Simulation, and ADMET Proprieties of Novel Pteridinone Derivatives as PLK1 Inhibitors for the Treatment of Prostate Cancer |
title_full_unstemmed | 3D-QSAR Studies, Molecular Docking, Molecular Dynamic Simulation, and ADMET Proprieties of Novel Pteridinone Derivatives as PLK1 Inhibitors for the Treatment of Prostate Cancer |
title_short | 3D-QSAR Studies, Molecular Docking, Molecular Dynamic Simulation, and ADMET Proprieties of Novel Pteridinone Derivatives as PLK1 Inhibitors for the Treatment of Prostate Cancer |
title_sort | 3d-qsar studies, molecular docking, molecular dynamic simulation, and admet proprieties of novel pteridinone derivatives as plk1 inhibitors for the treatment of prostate cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865323/ https://www.ncbi.nlm.nih.gov/pubmed/36676076 http://dx.doi.org/10.3390/life13010127 |
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