Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach
Abstract 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, breas...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-45175-3 |
| _version_ | 1797452724086767616 |
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| author | Nisarg Rana Dhaval Patel Meet Parmar Nandini Mukherjee Prakash C. Jha Anu Manhas |
| author_facet | Nisarg Rana Dhaval Patel Meet Parmar Nandini Mukherjee Prakash C. Jha Anu Manhas |
| author_sort | Nisarg Rana |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-09T15:11:47Z |
| format | Article |
| id | doaj.art-75c1638ccbbc4faf9dc307937ff1f25c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-09T15:11:47Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-75c1638ccbbc4faf9dc307937ff1f25c2023-11-26T13:18:32ZengNature PortfolioScientific Reports2045-23222023-10-0113112210.1038/s41598-023-45175-3Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approachNisarg Rana0Dhaval Patel1Meet Parmar2Nandini Mukherjee3Prakash C. Jha4Anu Manhas5Department of Chemistry, School of Energy Technology, Pandit Deendayal Energy UniversityDepartment of Industrial Biotechnology, Gujarat Biotechnology UniversityDepartment of Industrial Biotechnology, Gujarat Biotechnology UniversityDepartment of Chemistry, School of Energy Technology, Pandit Deendayal Energy UniversitySchool of Applied Material Sciences, Central University of GujaratDepartment of Chemistry, School of Energy Technology, Pandit Deendayal Energy UniversityAbstract 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.https://doi.org/10.1038/s41598-023-45175-3 |
| spellingShingle | Nisarg Rana Dhaval Patel Meet Parmar Nandini Mukherjee Prakash C. Jha Anu Manhas Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach Scientific Reports |
| 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 |
| url | https://doi.org/10.1038/s41598-023-45175-3 |
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