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Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach
Cancer has been viewed as one of the deadliest diseases worldwide. Among various types of cancer, breast cancer is the most common type of cancer in women. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a promising druggable target and is overexpressed in cancerous cells, like, breast cancer....
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10593809/ https://www.ncbi.nlm.nih.gov/pubmed/37872243 http://dx.doi.org/10.1038/s41598-023-45175-3 |
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author | Rana, Nisarg Patel, Dhaval Parmar, Meet Mukherjee, Nandini Jha, Prakash C. Manhas, Anu |
author_facet | Rana, Nisarg Patel, Dhaval Parmar, Meet Mukherjee, Nandini Jha, Prakash C. Manhas, Anu |
author_sort | Rana, Nisarg |
collection | PubMed |
description | Cancer has been viewed as one of the deadliest diseases worldwide. Among various types of cancer, breast cancer is the most common type of cancer in women. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a promising druggable target and is overexpressed in cancerous cells, like, breast cancer. We conducted structure-based modeling on the allosteric site of the enzyme. Targeting the allosteric site avoids the problem of drug resistance. Pharmacophore modeling, molecular docking, HYDE assessment, drug-likeness, ADMET predictions, simulations, and free-energy calculations were performed. The RMSD, RMSF, RoG, SASA, and Hydrogen-bonding studies showed that seven candidates displayed stable behaviour. As per the literature, average superimposed simulated structures revealed a similar protein conformational change in the αEʹ-βfʹ loop, causing its displacement away from the allosteric site. The MM-PBSA showed tight binding of six compounds with the allosteric pocket. The effect of inhibitors interacting in the allosteric site causes a decrease in the binding energy of J49 (active-site inhibitor), suggesting the effect of allosteric binding. The PCA and FEL analysis revealed the significance of the docked compounds in the stable behaviour of the complexes. The outcome can contribute to the development of potential natural products with drug-like properties that can inhibit the MTHFD2 enzyme. |
format | Online Article Text |
id | pubmed-10593809 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-105938092023-10-25 Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach Rana, Nisarg Patel, Dhaval Parmar, Meet Mukherjee, Nandini Jha, Prakash C. Manhas, Anu Sci Rep Article Cancer has been viewed as one of the deadliest diseases worldwide. Among various types of cancer, breast cancer is the most common type of cancer in women. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a promising druggable target and is overexpressed in cancerous cells, like, breast cancer. We conducted structure-based modeling on the allosteric site of the enzyme. Targeting the allosteric site avoids the problem of drug resistance. Pharmacophore modeling, molecular docking, HYDE assessment, drug-likeness, ADMET predictions, simulations, and free-energy calculations were performed. The RMSD, RMSF, RoG, SASA, and Hydrogen-bonding studies showed that seven candidates displayed stable behaviour. As per the literature, average superimposed simulated structures revealed a similar protein conformational change in the αEʹ-βfʹ loop, causing its displacement away from the allosteric site. The MM-PBSA showed tight binding of six compounds with the allosteric pocket. The effect of inhibitors interacting in the allosteric site causes a decrease in the binding energy of J49 (active-site inhibitor), suggesting the effect of allosteric binding. The PCA and FEL analysis revealed the significance of the docked compounds in the stable behaviour of the complexes. The outcome can contribute to the development of potential natural products with drug-like properties that can inhibit the MTHFD2 enzyme. Nature Publishing Group UK 2023-10-23 /pmc/articles/PMC10593809/ /pubmed/37872243 http://dx.doi.org/10.1038/s41598-023-45175-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Rana, Nisarg Patel, Dhaval Parmar, Meet Mukherjee, Nandini Jha, Prakash C. Manhas, Anu Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach |
title | Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach |
title_full | Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach |
title_fullStr | Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach |
title_full_unstemmed | Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach |
title_short | Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach |
title_sort | targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (mthfd2) to identify natural product inhibitors via structure-based computational approach |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10593809/ https://www.ncbi.nlm.nih.gov/pubmed/37872243 http://dx.doi.org/10.1038/s41598-023-45175-3 |
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