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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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.
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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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