The AAPS Journal

, Volume 19, Issue 4, pp 1235–1248 | Cite as

Integrated In Silico Fragment-Based Drug Design: Case Study with Allosteric Modulators on Metabotropic Glutamate Receptor 5

  • Yuemin Bian
  • Zhiwei Feng
  • Peng Yang
  • Xiang-Qun Xie
Research Article


GPCR allosteric modulators target at the allosteric binding pockets of G protein-coupled receptors (GPCRs) with indirect influence on the effects of an orthosteric ligand. Such modulators exhibit significant advantages compared to the corresponding orthosteric ligands, including better chemical tractability or physicochemical properties, improved selectivity, and reduced risk of oversensitization towards their receptors. Metabotropic glutamate receptor 5 (mGlu5), a member of class C GPCRs, is a promising therapeutic target for treating many central nervous system diseases. The crystal structure of mGlu5 in the complex with the negative allosteric modulator mavoglurant was recently reported, providing a fundamental model for designing new allosteric modulators. Computational fragment-based drug discovery represents a powerful scaffold-hopping and lead structure-optimization tool for drug design. In the present work, a set of integrated computational methodologies was first used, such as fragment library generation and retrosynthetic combinatorial analysis procedure (RECAP) for novel compound generation. Then, the compounds generated were assessed by benchmark dataset verification, docking studies, and QSAR model simulation. Subsequently, structurally diverse compounds, with reported or unreported scaffolds, can be observed from top 20 in silico synthesized compounds, which were predicted to be potential mGlu5 modulators. In silico compounds with reported scaffolds may fill SAR holes in known, patented series of mGlu5 modulators. And the generation of compounds without reported tests on mGluR indicates that our approach is doable for exploring and designing novel compounds. Our case study of designing allosteric modulators on mGlu5 demonstrated that the established computational fragment-based approach is a useful methodology for facilitating new compound design in the future.


allosteric modulator computational fragment-based drug discovery GPCRs metabotropic glutamate receptor 5 



Authors would like to acknowledge the funding supports to the Xie laboratory from the NIH NIDA (P30 DA035778A1), NIH (R01 DA025612), and DOD (W81XWH-16-1-0490).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Supplementary material

12248_2017_93_MOESM1_ESM.docx (852 kb)
Supplementary table 1 (DOCX 851 kb)
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Supplementary table 2 (DOCX 548 kb)
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Supplementary table 3 (DOCX 1180 kb)
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Supplementary table 4 (DOCX 464 kb)
12248_2017_93_MOESM5_ESM.docx (555 kb)
Supplementary table 5 (DOCX 555 kb)


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Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Yuemin Bian
    • 1
    • 2
    • 3
  • Zhiwei Feng
    • 1
    • 2
    • 3
  • Peng Yang
    • 1
    • 2
    • 3
  • Xiang-Qun Xie
    • 1
    • 2
    • 3
    • 4
    • 5
  1. 1.Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of PharmacyUniversity of PittsburghPittsburghUSA
  2. 2.NIDA National Center of Excellence for Computational Drug Abuse ResearchUniversity of PittsburghPittsburghUSA
  3. 3.Drug Discovery InstituteUniversity of PittsburghPittsburghUSA
  4. 4.Department of Computational Biology, School of MedicineUniversity of PittsburghPittsburghUSA
  5. 5.Department of Structural Biology, School of MedicineUniversity of PittsburghPittsburghUSA

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