Abstract
Purpose: To explore in silico methods to search for the best reported non-nucleoside DNA methyltransferase 1 (DNMT1) inhibitor of epimutation in gastric cancer.Methods: A dataset of reported non-nucleoside DNMT1 inhibitors was used to target the active site of crystallized DNMT1 protein. Molecular docking simulations were carried out using AutoDock 4.2.6 l. The results were analyzed using Discovery studio visualizer.Results: In silico analysis of known natural non-nucleoside DNMT1 inhibitors gave genistein as the top ranked compound with ΔG of -6.39 Kcal/mol. Further, the results indicated that epigallocatechin gallate and curcumin are poor non-nucleoside DNMT1 inhibitors, as the in silico data suggest that they failed to bind to the catalytic site of DNMT1.Conclusion: The results indicate that genistein is the top rated compound for DNMT1 inhibition. Previous in vitro and in vivo work by other researchers seem to validate the findings of the study.Keywords: Epi-mutation, DNA methyltransferase, Non-nucleoside, DNMT1 inhibitor, Docking
Highlights
The inhibition of DNA methyltransferase1 (DNMT1) can be achieved by two inhibitory mechanisms: enzyme trapping achieved by nucleoside inhibitors and enzyme blocking by non-nucleoside inhibitors
The data generated by analysis of these compounds with recently developed crystallographic structure showed that daidzene was the only compound interacting with the active site CYS1226, epigallocatechin gallate showed no interaction with the DNMT1 protein
Further analysis indicated that Epigallocatechin gallate is over hyped non-nucleoside DNMT1 inhibitor, as the results showed that it fails to interact with the catalytic scaffold of DNMT1
Summary
The inhibition of DNA methyltransferase (DNMT1) can be achieved by two inhibitory mechanisms: enzyme trapping achieved by nucleoside inhibitors and enzyme blocking by non-nucleoside inhibitors. 5-azacytosine was shown to influence cellular differentiation by incorporation into DNA, and to acts as a nucleoside inhibitor [3]. This inhibitor was found to affect a variety of RNA functions and cause certain toxic effects [4]. Another DNMT1 inhibitor, 5-aza-2 ′ -deoxycytidine (i.e., decitabine), is a deoxyribose analogue of 5azacytidine and has no effect on RNA function, but shows substantial toxic effects [5] Another addition to the group of nucleoside DNMT1 inhibitors is zebularine [6], which is a derivative of 5-azacytidine. This analog is more stable than others and its toxicity is less severe than the others [7]
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