Evaluation of potential inhibitors of squalene synthase based on virtual screening and in vitro studies

Comput Biol Chem. 2019 Jun:80:390-397. doi: 10.1016/j.compbiolchem.2019.04.008. Epub 2019 Apr 29.

Abstract

Squalene synthase (SQS) is a potential target for hyperlipidemia treatment. To identify novel chemical scaffolds of SQS inhibitors, we generated 3D-QSAR pharmacophore models using HypoGen. The best quantitative pharmacophore model, Hypo 1, was selected for virtual screening using two chemical databases, Specs and Traditional Chinese Medicine database (TCM). The best-mapped hit compounds were then subjected to filtering by Lipinski's rule of five and docking studies to refine the hits. Finally, five compounds were selected from the top-ranked hit compounds for SQS inhibitory assay in vitro. Three of these compounds could inhibit SQS in vitro, and should be further evaluated pre-clinically as a treatment for hyperlipidemia.

Keywords: 3D-QSAR; In vitro evaluation; Molecular docking; Squalene synthase inhibitor; Virtual screening.

MeSH terms

  • Catalytic Domain
  • Datasets as Topic
  • Drug Design
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Farnesyl-Diphosphate Farnesyltransferase / antagonists & inhibitors*
  • Farnesyl-Diphosphate Farnesyltransferase / chemistry
  • Farnesyl-Diphosphate Farnesyltransferase / metabolism*
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Binding
  • Quantitative Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Farnesyl-Diphosphate Farnesyltransferase