Novel Scaffold Identification of mGlu1 Receptor Negative Allosteric Modulators Using a Hierarchical Virtual Screening Approach.
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.
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 136-791, Korea.|Department of Biological Chemistry, School of Science, Korea University of Science and Technology, 52 Eoeun dong, Yuseong-gu, Daejeon, 305-333, Korea.
Jae Wan
JW
Jang
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 136-791, Korea.|Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul, 120-749, Korea.
Nam-Chul
NC
Cho
Department of Applied Chemistry, Hanyang University, Ansan, Gyeonggi-do, 15588, Korea.
Sun-Joon
SJ
Min
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 136-791, Korea.|Department of Biological Chemistry, School of Science, Korea University of Science and Technology, 52 Eoeun dong, Yuseong-gu, Daejeon, 305-333, Korea.
Yong Seo
YS
Cho
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 136-791, Korea.|Department of Biological Chemistry, School of Science, Korea University of Science and Technology, 52 Eoeun dong, Yuseong-gu, Daejeon, 305-333, Korea.
Ki Duk
KD
Park
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 136-791, Korea.
Seon Hee
SH
Seo
Department of Biotechnology, Yonsei University, Seodaemun-gu, Seoul, 120-749, Korea.
Kyoung Tai
KT
No
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 5, Seongbuk-gu, Seoul, 136-791, Korea.|Department of Biological Chemistry, School of Science, Korea University of Science and Technology, 52 Eoeun dong, Yuseong-gu, Daejeon, 305-333, Korea.
Ae Nim
AN
Pae
D000494:Allosteric Regulation; D000495:Allosteric Site; D000595:Amino Acid Sequence; D019540:Area Under Curve; D001499:Bayes Theorem; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D012372:ROC Curve; D050637:Receptors, Dopamine D3 / Q000737:chemistry; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D060388:Support Vector Machine
D050637:Receptors, Dopamine D3; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1
hierarchical high-throughput virtual screening; mGluR1 negative allosteric modulators