Cracking a cancer code DNA methylation in epigenetic modification: an in-silico approach on efficacy assessment of Sri Lanka-oriented nutraceuticals

Abstract

DNA methyltransferase (DNMTs) are essential epigenetic modifiers that play a critical role in gene regulation. These enzymes add a methyl group to cytosine’s 5'-carbon, specifically within CpG dinucleotides, using S-adenosyl-L-methionine. Abnormal overexpression of DNMTs can alter the gene expression patterns and contribute to cancer development in the human body. Therefore, the inhibition of DNMT is a promising therapeutic approach to cancer treatment. This study was aimed to identify potential nutraceutical inhibitors from the Sri Lanka Flora database using computational methods, which provided an atomic-level description of the drug binding site and examined the interactions between nutraceuticals and amino acids of the DNMT enzyme. A series of nutraceuticals from Sri Lanka-oriented plants were selected and evaluated to assess their inhibitory effects on DNMT using absorption, distribution, metabolism, excretion and toxicity analysis, virtual screening, molecular docking, molecular dynamics simulation and trajectory analysis. Azacitidine, a DNMT inhibitor approved by the US Food and Drug Administration, was selected as a reference inhibitor. The complexes with more negative binding energies were selected and further assessed for their potency. Seven molecules were identified from 200 nutraceuticals, demonstrating significantly negative binding energies against the DNMT enzyme. Various trajectory analyses were conducted to investigate the stability of the DNMT enzyme. The results indicated that petchicine (NP#0003), ouregidione (NP#0011) and azacitidine increased the stability of the DNMT enzyme. Consequently, these two nutraceuticals showed inhibitory efficacies similar to azacitidine, making them potential candidates for therapeutic interventions targeting DNMT enzyme-related cancers. Additional bioassay testing is recommended to confirm the efficacies of these nutraceuticals and explore their applicability in clinical treatments.

Communicated by Ramaswamy H. Sarma

Keywords:

• DNMT enzyme
• Sri Lanka Flora database
• azacitidine
• ADMET
• petchicine

Acknowledgments

This research work is dedicated to Emeritus Professor G. M. Kamal B. Gunaherath, an eminent scientist and accomplished researcher renowned for his expertise in natural product chemistry in Sri Lanka.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data are available within the article or its supplementary materials.

Additional information

Funding

This work was supported by the Faculty Research Grant 2022, The Open University of Sri Lanka.