Mechanisms of DNA methyltransferase-inhibitor interactions: Procyanidin B2 shows new promise for therapeutic intervention of cancer

- DNMTs are potential anticancer drug development targets.
- Molecular docking of inhibitors of DNMTs using four different algorithms was done.
- EGCG had the highest binding interaction with DNMTs.
- EGCG analogue, procyanidin B2 exhibit the best binding energy scores and simulation.
- Procyanidin B2 reverses the DNMTs function and helps expression of silenced genes.

DNA methyltransferases (DNMTs) is a key epigenetic enzyme for pharmacological manipulation and is employed in cancer reprogramming. During past few years multiple strategies have been implemented to excavate epigenetic compounds targeting DNMTs. In light of the emerging concept of chemoinformatics, molecular docking and simulation studies have been employed to accelerate the development of DNMT inhibitors. Among the DNMT inhibitors known till date, epigallocathechin-3-gallate (EGCG) was identified to be effective in reducing DNMT activity. However, the broad spectrum of EGCG to other diseases and variable target enzymes offers some limitations. In view of this, 32 EGCG analogues were screened at S-Adnosyl-l-homocysteine (SAH) binding pocket of DNMTs and procyanidin B2-3, 3′-di-O-gallate (procyanidin B2) was obtained as potent inhibitor having medicinally relevant chemical space. Further, in vitro analysis demonstrates the efficiency of procyanidin B2 in attenuating DNMT activity at IC50 of 6.88 ± 0.647 μM and subsequently enhancing the expression of DNMT target genes, E-cadherin, Maspin and BRCA1. Moreover, the toxic property of procyanidin B2 towards triple negative breast cancer cells to normal cells offers platform for pre-clinical trial and an insight to the treatment of cancer.

The pharmacological inhibition of DNA methyltransferases offers a new dimension to chemotherapeutic prevention of cancers. The existing DNMT inhibitors lack high specificity. The virtual screening of EGCG analogues were carried out which led to identification of procyanidin B2 as novel compound against DNMT. The in silico findings were substantiated by in vitro analysis constituting cell viability assay, gene expression analysis and DNMT enzyme activity assay. Procyanidin B2 was identified to inhibit DNMT activity at IC50 value of 6.88 ± 0.647 μM.