Jang, Jae Wan Cho, Nam-Chul Min, Sun-Joon Cho, Yong Seo Park, Ki Duk Seo, Seon Hee No, Kyoung Tai Pae, Ae Nim 2024-01-20T05:02:14Z 2024-01-20T05:02:14Z 2021-09-05 2016-02 1747-0277 https://pubs.kist.re.kr/handle/201004/124441 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 naive 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. English WILEY PROTEIN-COUPLED RECEPTORS A(2A) ADENOSINE RECEPTOR SUPPORT VECTOR MACHINES 2ND EXTRACELLULAR LOOP CRYSTAL-STRUCTURE ACTIVATION MECHANISM POTENTIAL TREATMENT BIOLOGICAL PROFILE KINASE INHIBITORS MOLECULAR DOCKING Novel Scaffold Identification of mGlu1 Receptor Negative Allosteric Modulators Using a Hierarchical Virtual Screening Approach Article 10.1111/cbdd.12654 1 CHEMICAL BIOLOGY & DRUG DESIGN, v.87, no.2, pp.239 - 256 CHEMICAL BIOLOGY & DRUG DESIGN 87 2 239 256 scie scopus 000370485300009 2-s2.0-84957310327 Biochemistry & Molecular Biology Chemistry, Medicinal Biochemistry & Molecular Biology Pharmacology & Pharmacy Article PROTEIN-COUPLED RECEPTORS A(2A) ADENOSINE RECEPTOR SUPPORT VECTOR MACHINES 2ND EXTRACELLULAR LOOP CRYSTAL-STRUCTURE ACTIVATION MECHANISM POTENTIAL TREATMENT BIOLOGICAL PROFILE KINASE INHIBITORS MOLECULAR DOCKING hierarchical high-throughput virtual screening mGluR1 negative allosteric modulators