QSAR-driven rational design of novel DNA methyltransferase 1 inhibitors.

Abstract:

:DNA 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.

journal_name

EXCLI J

journal_title

EXCLI journal

authors

Phanus-Umporn C,Prachayasittikul V,Nantasenamat C,Prachayasittikul S,Prachayasittikul V

doi

10.17179/excli2020-1096

subject

Has Abstract

pub_date

2020-04-02 00:00:00

pages

458-475

issn

1611-2156

pii

Doc458

journal_volume

19

pub_type

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