The use of virtual screening and differential scanning fluorimetry for the rapid identification of fragments active against MEK1

Bioorg Med Chem Lett. 2013 Jun 15;23(12):3620-6. doi: 10.1016/j.bmcl.2013.04.003. Epub 2013 Apr 10.

Abstract

We report the analysis of an in-house fragment screening campaign for the oncology target MEK1. The application of virtual screening (VS) as a primary fragment screening approach, followed by biophysical validation using differential screening fluorimetry (DSF), with resultant binding mode determination by X-ray crystallography (X-ray), is presented as the most time and cost-effective combination of in silico and in vitro methods to identify fragments. We demonstrate the effectiveness of the VS-DSF workflow for the early identification of fragments to both 'jump-start' the drug discovery project and to complement biochemical screening data.

Publication types

  • Letter

MeSH terms

  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical / methods
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Fluorometry / methods*
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Kinase 1 / chemistry
  • MAP Kinase Kinase 1 / metabolism
  • Models, Molecular
  • Phosphorylation
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • MAP Kinase Kinase 1