Performance of a docking/molecular dynamics protocol for virtual screening of nutlin-class inhibitors of Mdmx

J Mol Graph Model. 2017 Jun;74:54-60. doi: 10.1016/j.jmgm.2017.02.014. Epub 2017 Feb 24.

Abstract

A virtual screening protocol involving docking and molecular dynamics has been tested against the results of fluorescence polarization assays testing the potency of a series of compounds of the nutlin class for inhibition of the interaction between p53 and Mdmx, an interaction identified as a driver of certain cancers. The protocol uses a standard docking method (AutoDock) with a cutoff based on the AutoDock score (ADscore), followed by molecular dynamics simulation with a cutoff based on root-mean-square-deviation (RMSD) from the docked pose. An analysis of the experimental and computational results shows modest performance of ADscore alone, but dramatically improved performance when RMSD is also used.

Keywords: Docking; Fluorescence polarization; Mdm4; Mdmx; Molecular dynamics simulations; Nutlin; Virtual screening.

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Binding Sites
  • Cell Cycle Proteins
  • Drug Screening Assays, Antitumor / methods
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Imidazoles / chemistry*
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / chemistry
  • Piperazines / chemistry*
  • Protein Binding
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / chemistry

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Imidazoles
  • MDM4 protein, human
  • Nuclear Proteins
  • Piperazines
  • Proto-Oncogene Proteins
  • nutlin 3