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Sequence-structure functional implications and molecular simulation of high deleterious nonsynonymous substitutions in IDH1 revealed the mechanism of drug resistance in glioma

In the past few years, various somatic point mutations of isocitrate dehydrogenase (IDH) encoding genes (IDH1 and IDH2) have been identified in a broad range of cancers, including glioma. Despite the important function of IDH1 in tumorigenesis and its very polymorphic nature, it is not yet clear how...

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Autores principales: Suleman, Muhammad, Umme-I-Hani, Syeda, Salman, Muhammad, Aljuaid, Mohammed, Khan, Abbas, Iqbal, Arshad, Hussain, Zahid, Ali, Syed Shujait, Ali, Liaqat, Sher, Hassan, Waheed, Yasir, Wei, Dong-Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9523485/
https://www.ncbi.nlm.nih.gov/pubmed/36188571
http://dx.doi.org/10.3389/fphar.2022.927570
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author Suleman, Muhammad
Umme-I-Hani, Syeda
Salman, Muhammad
Aljuaid, Mohammed
Khan, Abbas
Iqbal, Arshad
Hussain, Zahid
Ali, Syed Shujait
Ali, Liaqat
Sher, Hassan
Waheed, Yasir
Wei, Dong-Qing
author_facet Suleman, Muhammad
Umme-I-Hani, Syeda
Salman, Muhammad
Aljuaid, Mohammed
Khan, Abbas
Iqbal, Arshad
Hussain, Zahid
Ali, Syed Shujait
Ali, Liaqat
Sher, Hassan
Waheed, Yasir
Wei, Dong-Qing
author_sort Suleman, Muhammad
collection PubMed
description In the past few years, various somatic point mutations of isocitrate dehydrogenase (IDH) encoding genes (IDH1 and IDH2) have been identified in a broad range of cancers, including glioma. Despite the important function of IDH1 in tumorigenesis and its very polymorphic nature, it is not yet clear how different nsSNPs affect the structure and function of IDH1. In the present study, we employed different machine learning algorithms to screen nsSNPs in the IDH1 gene that are highly deleterious. From a total of 207 SNPs, all of the servers classified 80 mutations as deleterious. Among the 80 deleterious mutations, 14 were reported to be highly destabilizing using structure-based prediction methods. Three highly destabilizing mutations G15E, W92G, and I333S were further subjected to molecular docking and simulation validation. The docking results and molecular simulation analysis further displayed variation in dynamics features. The results from molecular docking and binding free energy demonstrated reduced binding of the drug in contrast to the wild type. This, consequently, shows the impact of these deleterious substitutions on the binding of the small molecule. PCA (principal component analysis) and FEL (free energy landscape) analysis revealed that these mutations had caused different arrangements to bind small molecules than the wild type where the total internal motion is decreased, thus consequently producing minimal binding effects. This study is the first extensive in silico analysis of the IDH1 gene that can narrow down the candidate mutations for further validation and targeting for therapeutic purposes.
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spelling pubmed-95234852022-10-01 Sequence-structure functional implications and molecular simulation of high deleterious nonsynonymous substitutions in IDH1 revealed the mechanism of drug resistance in glioma Suleman, Muhammad Umme-I-Hani, Syeda Salman, Muhammad Aljuaid, Mohammed Khan, Abbas Iqbal, Arshad Hussain, Zahid Ali, Syed Shujait Ali, Liaqat Sher, Hassan Waheed, Yasir Wei, Dong-Qing Front Pharmacol Pharmacology In the past few years, various somatic point mutations of isocitrate dehydrogenase (IDH) encoding genes (IDH1 and IDH2) have been identified in a broad range of cancers, including glioma. Despite the important function of IDH1 in tumorigenesis and its very polymorphic nature, it is not yet clear how different nsSNPs affect the structure and function of IDH1. In the present study, we employed different machine learning algorithms to screen nsSNPs in the IDH1 gene that are highly deleterious. From a total of 207 SNPs, all of the servers classified 80 mutations as deleterious. Among the 80 deleterious mutations, 14 were reported to be highly destabilizing using structure-based prediction methods. Three highly destabilizing mutations G15E, W92G, and I333S were further subjected to molecular docking and simulation validation. The docking results and molecular simulation analysis further displayed variation in dynamics features. The results from molecular docking and binding free energy demonstrated reduced binding of the drug in contrast to the wild type. This, consequently, shows the impact of these deleterious substitutions on the binding of the small molecule. PCA (principal component analysis) and FEL (free energy landscape) analysis revealed that these mutations had caused different arrangements to bind small molecules than the wild type where the total internal motion is decreased, thus consequently producing minimal binding effects. This study is the first extensive in silico analysis of the IDH1 gene that can narrow down the candidate mutations for further validation and targeting for therapeutic purposes. Frontiers Media S.A. 2022-09-16 /pmc/articles/PMC9523485/ /pubmed/36188571 http://dx.doi.org/10.3389/fphar.2022.927570 Text en Copyright © 2022 Suleman, Umme-I-Hani, Salman, Aljuaid, Khan, Iqbal, Hussain, Ali, Ali, Sher, Waheed and Wei. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Suleman, Muhammad
Umme-I-Hani, Syeda
Salman, Muhammad
Aljuaid, Mohammed
Khan, Abbas
Iqbal, Arshad
Hussain, Zahid
Ali, Syed Shujait
Ali, Liaqat
Sher, Hassan
Waheed, Yasir
Wei, Dong-Qing
Sequence-structure functional implications and molecular simulation of high deleterious nonsynonymous substitutions in IDH1 revealed the mechanism of drug resistance in glioma
title Sequence-structure functional implications and molecular simulation of high deleterious nonsynonymous substitutions in IDH1 revealed the mechanism of drug resistance in glioma
title_full Sequence-structure functional implications and molecular simulation of high deleterious nonsynonymous substitutions in IDH1 revealed the mechanism of drug resistance in glioma
title_fullStr Sequence-structure functional implications and molecular simulation of high deleterious nonsynonymous substitutions in IDH1 revealed the mechanism of drug resistance in glioma
title_full_unstemmed Sequence-structure functional implications and molecular simulation of high deleterious nonsynonymous substitutions in IDH1 revealed the mechanism of drug resistance in glioma
title_short Sequence-structure functional implications and molecular simulation of high deleterious nonsynonymous substitutions in IDH1 revealed the mechanism of drug resistance in glioma
title_sort sequence-structure functional implications and molecular simulation of high deleterious nonsynonymous substitutions in idh1 revealed the mechanism of drug resistance in glioma
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9523485/
https://www.ncbi.nlm.nih.gov/pubmed/36188571
http://dx.doi.org/10.3389/fphar.2022.927570
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