In silico approaches to identify the potential inhibitors of glutamate carboxypeptidase II (GCPII) for neuroprotection

J Theor Biol. 2016 Oct 7:406:137-42. doi: 10.1016/j.jtbi.2016.07.016. Epub 2016 Jul 16.

Abstract

To develop a potential inhibitor for glutamate carboxypeptidase II (GCPII) effective against all the eight common genetic variants reported, PyMOL molecular visualization system was used to generate models of variants using the crystal structure of GCPII i.e. 2OOT as a template. High-throughput virtual screening of 29 compounds revealed differential efficacy across the eight genetic variants (pIC50: 4.70 to 10.22). Pharmacophore analysis and quantitative structure-activity relationship (QSAR) studies revealed a urea-based N-acetyl aspartyl glutamate (NAAG) analogue as more potent inhibitor, which was effective across all the genetic variants of GCPII as evidenced by glide scores (-4.32 to -7.08) and protein-ligand interaction plots (13 interactions in wild GCPII). This molecule satisfied Lipinski rule of five and rule of three for drug-likeliness. Being a NAAG-analogue, this molecule might confer neuroprotection by inhibiting glutamatergic neurotransmission mediated by N-acetylated alpha-linked acidic dipeptidase (NAALADase), a splice variant of GCPII.

Keywords: Glutamate carboxypeptidase II; Glutamatergic transmission; N-acetyl aspartyl glutamate; Urea-based NAAG-analogue.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation*
  • Genetic Variation
  • Glutamate Carboxypeptidase II / antagonists & inhibitors*
  • Glutamate Carboxypeptidase II / chemistry
  • Ligands
  • Models, Molecular
  • Neuroprotection / drug effects*
  • Protease Inhibitors / analysis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Quantitative Structure-Activity Relationship

Substances

  • Ligands
  • Protease Inhibitors
  • Glutamate Carboxypeptidase II