Structure-based virtual screening as a tool for the identification of novel inhibitors against Mycobacterium tuberculosis 3-dehydroquinate dehydratase

J Mol Graph Model. 2015 Jul;60:124-31. doi: 10.1016/j.jmgm.2015.05.001. Epub 2015 May 11.

Abstract

3-Dehydroquinate dehydratase (DHQase), the third enzyme of the shikimate pathway, catalyzes the reversible reaction of 3-dehydroquinate into 3-dehydroshikimate. The aim of the present study was to identify new drug-like molecules as inhibitors for Mycobacterium tuberculosis DHQase employing structure-based pharmacophore modeling technique using an in house database consisting of about 2500 small molecules. Further the pharmacophore models were validated using enrichment calculations, and finally three models were employed for high-throughput virtual screening and docking to identify novel small molecules as DHQase inhibitors. Five compounds were identified, out of which, one molecule (Lead 1) showed 58% inhibition at 50μ M concentration in the Mtb DHQase assay. Chemical derivatives of the Lead 1 when tested evolved top two hits with IC50s of 17.1 and 31.5 μM as well as MIC values of 25 and 6.25 μg/mL respectively and no cytotoxicity up to 100 μM concentration.

Keywords: DHQase; Drug discovery; Shikimate pathway; Tuberculosis; Virtual screening.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / isolation & purification
  • Antitubercular Agents / toxicity
  • Bacterial Proteins / antagonists & inhibitors*
  • Datasets as Topic
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / isolation & purification
  • Enzyme Inhibitors / toxicity
  • HEK293 Cells
  • High-Throughput Screening Assays*
  • Humans
  • Hydro-Lyases / antagonists & inhibitors*
  • Inhibitory Concentration 50
  • Ligands
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Docking Simulation*
  • Molecular Structure
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / enzymology*
  • Protein Binding
  • Structure-Activity Relationship
  • User-Computer Interface*

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Ligands
  • Hydro-Lyases
  • 3-dehydroquinate dehydratase