Identification of a potential DNA methyltransferase (DNMT) inhibitor
<p dir="ltr">DNA methyltransferases (DNMTs) play an important role in the epigenetic regulation of gene expression through the methylation of DNA. Since hypermethylation and consequent suppression of tumor suppressor genes are associated with cancer development and progression, DNA h...
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2023
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| _version_ | 1864513528290869248 |
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| author | Zainab Jan (17306614) |
| author2 | Wesam S. Ahmed (10170053) Kabir H. Biswas (5705864) Puthen Veettil Jithesh (12040358) |
| author2_role | author author author |
| author_facet | Zainab Jan (17306614) Wesam S. Ahmed (10170053) Kabir H. Biswas (5705864) Puthen Veettil Jithesh (12040358) |
| author_role | author |
| dc.creator.none.fl_str_mv | Zainab Jan (17306614) Wesam S. Ahmed (10170053) Kabir H. Biswas (5705864) Puthen Veettil Jithesh (12040358) |
| dc.date.none.fl_str_mv | 2023-07-09T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1080/07391102.2023.2233637 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Identification_of_a_potential_DNA_methyltransferase_DNMT_inhibitor/25150952 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics Biomedical and clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences DNA methyltransferases DNMT inhibitors drug discovery DNA hypomethylating agents virtual screening cancer therapy |
| dc.title.none.fl_str_mv | Identification of a potential DNA methyltransferase (DNMT) inhibitor |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">DNA methyltransferases (DNMTs) play an important role in the epigenetic regulation of gene expression through the methylation of DNA. Since hypermethylation and consequent suppression of tumor suppressor genes are associated with cancer development and progression, DNA hypomethylating agents (HMAs) such as DNMT inhibitors have been proposed for cancer therapy. Two nucleoside analogues approved for the treatment of hematological cancers, decitabine and azacytidine, have poor pharmacokinetic properties, and hence there is a critical need for identifying novel HMAs. Virtual screening of a library of ∼40,000 compounds from the ZINC database, followed by molecular docking of 4,000 compounds having potential druggable properties with DNMT1, DNMT3A and DNMT3B were performed. One unique inhibitor (ZINC167686681) was identified that successfully passed through the Lipinski Rule of 5, geometry constraints as well as ADME/Tox filters and having strong binding energy for DNMTs. Further, molecular dynamics simulations of the docked complexes showed detailed structural features critical for its binding with the DNMTs and the stability of their interaction. Our study identified a compound with potential druggable properties and predicted to bind and inhibit DNMTs. Further investigations involving cellular and animal models of ZINC167686681 will help in potentially taking it into clinical trials for the treatment of cancers.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Biomolecular Structure and Dynamics<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1080/07391102.2023.2233637" target="_blank">https://dx.doi.org/10.1080/07391102.2023.2233637</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_69ad6af7e98e186a5f459261391fab6d |
| identifier_str_mv | 10.1080/07391102.2023.2233637 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25150952 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Identification of a potential DNA methyltransferase (DNMT) inhibitorZainab Jan (17306614)Wesam S. Ahmed (10170053)Kabir H. Biswas (5705864)Puthen Veettil Jithesh (12040358)Biological sciencesGeneticsBiomedical and clinical sciencesOncology and carcinogenesisPharmacology and pharmaceutical sciencesDNA methyltransferasesDNMT inhibitorsdrug discoveryDNA hypomethylating agentsvirtual screeningcancer therapy<p dir="ltr">DNA methyltransferases (DNMTs) play an important role in the epigenetic regulation of gene expression through the methylation of DNA. Since hypermethylation and consequent suppression of tumor suppressor genes are associated with cancer development and progression, DNA hypomethylating agents (HMAs) such as DNMT inhibitors have been proposed for cancer therapy. Two nucleoside analogues approved for the treatment of hematological cancers, decitabine and azacytidine, have poor pharmacokinetic properties, and hence there is a critical need for identifying novel HMAs. Virtual screening of a library of ∼40,000 compounds from the ZINC database, followed by molecular docking of 4,000 compounds having potential druggable properties with DNMT1, DNMT3A and DNMT3B were performed. One unique inhibitor (ZINC167686681) was identified that successfully passed through the Lipinski Rule of 5, geometry constraints as well as ADME/Tox filters and having strong binding energy for DNMTs. Further, molecular dynamics simulations of the docked complexes showed detailed structural features critical for its binding with the DNMTs and the stability of their interaction. Our study identified a compound with potential druggable properties and predicted to bind and inhibit DNMTs. Further investigations involving cellular and animal models of ZINC167686681 will help in potentially taking it into clinical trials for the treatment of cancers.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Biomolecular Structure and Dynamics<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1080/07391102.2023.2233637" target="_blank">https://dx.doi.org/10.1080/07391102.2023.2233637</a></p>2023-07-09T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1080/07391102.2023.2233637https://figshare.com/articles/journal_contribution/Identification_of_a_potential_DNA_methyltransferase_DNMT_inhibitor/25150952CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/251509522023-07-09T03:00:00Z |
| spellingShingle | Identification of a potential DNA methyltransferase (DNMT) inhibitor Zainab Jan (17306614) Biological sciences Genetics Biomedical and clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences DNA methyltransferases DNMT inhibitors drug discovery DNA hypomethylating agents virtual screening cancer therapy |
| status_str | publishedVersion |
| title | Identification of a potential DNA methyltransferase (DNMT) inhibitor |
| title_full | Identification of a potential DNA methyltransferase (DNMT) inhibitor |
| title_fullStr | Identification of a potential DNA methyltransferase (DNMT) inhibitor |
| title_full_unstemmed | Identification of a potential DNA methyltransferase (DNMT) inhibitor |
| title_short | Identification of a potential DNA methyltransferase (DNMT) inhibitor |
| title_sort | Identification of a potential DNA methyltransferase (DNMT) inhibitor |
| topic | Biological sciences Genetics Biomedical and clinical sciences Oncology and carcinogenesis Pharmacology and pharmaceutical sciences DNA methyltransferases DNMT inhibitors drug discovery DNA hypomethylating agents virtual screening cancer therapy |