QSAR-driven rational design of novel DNA methyltransferase 1 inhibitors

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dc.contributor.authorPhanus-umporn, Chuleeporn
dc.contributor.authorPrachayasittikul, Veda
dc.contributor.authorNantasenamat, Chanin
dc.contributor.authorPrachayasittikul, Supaluk
dc.contributor.authorPrachayasittikul, Virapong
dc.date.accessioned2020-12-11T12:24:08Z
dc.date.available2020-12-11T12:24:08Z
dc.date.issued2020-04-02
dc.description.abstractDNA methylation, an epigenetic modification, is mediated by DNA methyltransferases (DNMTs), a family of enzymes. Inhibitions of these enzymes are considered a promising strategy for the treatment of several diseases. In this study, a quantitative structure-activity relationship (QSAR) modeling was employed to understand the structure-activity relationship (SAR) of currently available non-nucleoside DNMT1 inhibitors (i.e., indole and oxazoline/1,2-oxazole scaffolds). Two QSAR models were successfully constructed using multiple linear regression (MLR) and provided good predictive performance (R2Tr = 0.850-0.988 and R2CV = 0.672-0.869). Bond information content index (BIC1) and electronegativity (R6e+) are the most influential descriptors governing the activity of compounds. The constructed QSAR models were further applied for guiding a rational design of novel inhibitors. A novel set of 153 structurally modified compounds were designed in silico according to the important descriptors deduced from the QSAR finding, and their DNMT1 inhibitory activities were predicted. This result demonstrated that 86 newly designed inhibitors were predicted to elicit enhanced DNMT1 inhibitory activity when compared to their parent compounds. Finally, a set of promising compounds as potent DNMT1 inhibitors were highlighted to be further developed. The key SAR findings may also be beneficial for structural optimization to improve properties of the known inhibitors.en
dc.identifier.citationPhanus-umporn, C., Prachayasittikul, V., Nantasenamat, C., Prachayasittikul, S., & Prachayasittikul, V. (2020). QSAR-driven rational design of novel DNA methyltransferase 1 inhibitors. EXCLI Journal, 19, 458-475. https://doi.org/10.17179/excli2020-1096en
dc.identifier.issn1611-2156
dc.identifier.urihttp://hdl.handle.net/2003/39870
dc.identifier.urihttp://dx.doi.org/10.17877/DE290R-21761
dc.language.isoen
dc.publisherIfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmunden
dc.relation.ispartofseriesEXCLI Journal;Vol. 19 2020
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectDNA methyltransferase 1en
dc.subjectQSARen
dc.subjectComputer-aided drug designen
dc.subjectRational designen
dc.subjectStructural modificationen
dc.subjectEpigenetic modulatorsen
dc.subject.ddc610
dc.titleQSAR-driven rational design of novel DNA methyltransferase 1 inhibitorsen
dc.typeText
dc.type.publicationtypearticle
dcterms.accessRightsopen access
eldorado.dnb.zdberstkatid2132560-1
eldorado.identifier.urlhttps://www.excli.de/index.php/excli/article/view/2011
eldorado.secondarypublicationtrue

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