Chemometric modeling, docking and in silico design of triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors as antimalarials

Eur J Med Chem. 2010 Oct;45(10):4645-56. doi: 10.1016/j.ejmech.2010.07.034. Epub 2010 Jul 24.

Abstract

In the present work, QSAR and molecular docking studies have been performed on triazolopyrimidine-based dihydroorotate dehydrogenase (DHODH) inhibitors as antimalarial agents. The QSAR studies have been carried out using classical QSAR (physicochemical) approach using linear free energy related (LFER) model and molecular shape analysis using shape, spatial, electronic, thermodynamic and structural descriptors. Docking studies suggest that the 2-methyltriazolopyrimidine ring interacts with some polar and some nonpolar amino acids whereas the substituted phenyl ring binds with a hydrophobic pocket of the enzyme formed by some nonpolar amino acid residues. According to QSAR and molecular docking studies, we have designed some new compounds which showed good in silico predicted activity as per the developed QSAR models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / chemistry*
  • Antimalarials / pharmacology*
  • Drug Design
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Malaria / drug therapy
  • Malaria / enzymology
  • Models, Biological
  • Models, Molecular
  • Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors*
  • Oxidoreductases Acting on CH-CH Group Donors / metabolism
  • Plasmodium / drug effects
  • Plasmodium / enzymology*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Quantitative Structure-Activity Relationship
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • Antimalarials
  • Enzyme Inhibitors
  • Pyrimidines
  • Triazoles
  • Oxidoreductases Acting on CH-CH Group Donors
  • dihydroorotate dehydrogenase