Novel Scaffold Identification of mGlu1 Receptor Negative Allosteric Modulators Using a Hierarchical Virtual Screening Approach

Jae Wan Jang, Nam Chul Cho, Sun Joon Min, Yong Seo Cho, Ki Duk Park, Seon Hee Seo, Kyoung Tai No, Ae Nim Pae

Research output: Contribution to journalArticle

11 Citations (Scopus)


Metabotropic glutamate receptor 1 (mGluR1) is considered as an attractive drug target for neuropathic pain treatments. The hierarchical virtual screening approach for identifying novel scaffolds of mGluR1 allosteric modulators was performed using a homology model built with the dopamine D3 crystal structure as template. The mGluR1 mutagenesis data, conserved amino acid sequences across class A and class C GPCRs, and previously reported multiple sequence alignments of class C GPCRs to the rhodopsin template, were employed for the sequence alignment to overcome difficulties of model generation with low sequence identity of mGluR1 and dopamine D3. The structures refined by molecular dynamics simulations were employed for docking of Asinex commercial libraries after hierarchical virtual screening with pharmacophore and naïve Bayesian models. Five of 35 compounds experimentally evaluated using a calcium mobilization assay exhibited micromolar activities (IC50) with chemotype novelty that demonstrated the validity of our methods. A hierarchical structure and ligand-based virtual screening approach with homology model of class C GPCR based on dopamine D3 class A GPCR structure was successfully performed and applied to discover novel negative mGluR1 allosteric modulators.

Original languageEnglish
Pages (from-to)239-256
Number of pages18
JournalChemical Biology and Drug Design
Issue number2
Publication statusPublished - 2016 Feb


All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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