Hit identification of SMYD3 enzyme inhibitors using structure-based pharmacophore modeling

Future Med Chem. 2019 May;11(10):1107-1117. doi: 10.4155/fmc-2018-0462.

Abstract

Aim: SMYD3 enzyme is overexpressed in many types of cancer and its role in the methylation of cytoplasmic mitogen-activated protein kinase, kinase kinase 2 (MAP3K2), has been linked to promotion of Kras-driven cancer in pancreatic ductal and lung adenocarcinoma. Materials & methods: A hybrid 3D structure-based pharmacophore model was generated using crystal structures of SMYD3 complexed with sinefungin and was used to search for potential SMYD3 inhibitors through virtual screening of the Maybridge database. The retrieved hits from screening were further docked into the binding site of SMYD3 using CDOCKER docking algorithms. The top-ranked hits were selected and their inhibitory activity was evaluated. Results & conclusion: The results obtained helped us to find an SMYD3 small molecule hit inhibitor scaffold.

Keywords: SMYD3 enzyme; anticancer; assay development; hit identification; pharmacophore; structure-based drug design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / chemistry
  • Adenosine / pharmacology
  • Algorithms
  • Drug Discovery
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
  • Histone-Lysine N-Methyltransferase / chemistry
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Molecular Docking Simulation
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Histone-Lysine N-Methyltransferase
  • SMYD3 protein, human
  • Adenosine
  • sinefungin