Novel inhibitors design through structural investigations and simulation studies for human PKMTs (SMYD2) involved in cancer

SET and MYND domain-containing protein 2 (SMYD2) is a protein lysine methyltransferases (PKMTs) from family SMYD. It can regulate gene transcription by catalysing the methylation of lysine residues of protein substrates that play a significant role in oncogenesis. Inhibition of SMYD2 could lead to the proposal of new drugs for cancers, where it is involved. In this study, structure-based virtual screening was carried out for the identification of potential SMYD2 inhibitors. A subset of natural compounds (n = 98,071) from the ZINC database was screened by using a consensus docking approach and identified 391 potent compounds then evaluated based on ADMET parameters. Nine compounds were selected that chase line of drug-likeness criteria and re-docking. Based on docking score and protein-ligand interaction analysis, three compounds (ZINC03844862, ZINC08490711 and ZINC08764231) were identified as potential inhibitors. Finally, these three compounds were employed for 100 ns molecular dynamics simulation analysis to examine the structural stability with SMYD2. Moreover, RMSD, RMSF, H-bond, SASA and PCA analysis indicated the stable binding of potential compounds with SMYD2 structure. Computational approaches incorporated in this study provide novel putative SMYD2 inhibitors. These inhibitors could be potential leads to develop cancer therapeutics after in vivo and in vitro studies.

Automated summary

This study identified three potential SMYD2 inhibitors through virtual screening and molecular dynamics simulation, which could serve as potential leads in the development of cancer therapeutics.