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Computational Fragment-based Discovery of Allosteric Modulators on Metabotropic Glutamate Receptor 5

Bian, Yuemin (2017) Computational Fragment-based Discovery of Allosteric Modulators on Metabotropic Glutamate Receptor 5. Master's Thesis, University of Pittsburgh. (Unpublished)

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GPCR allosteric modulators target at the allosteric, “allo- from the Greek meaning "other", binding pockets of G protein-coupled receptors (GPCRs) with indirect influence on the effects of an agonist or inverse agonist. Such modulators exhibit significant advantages compared to the corresponding orthosteric ligands, including better chemical tractability or physicochemical properties, improved selectivity, and reduced risk of over-sensitization towards their receptors. Metabotropic glutamate receptor 5 (mGlu5), a member of GPCRs class C family, is a promising therapeutic target for treating many central nervous system (CNS) diseases. The crystal structure of mGlu5 in the complex with the negative allosteric modulator (NAM) mavoglurant was recently reported, providing a fundamental model for the design of new allosteric modulators. However, new NAM drugs are still in critical need for therapeutic uses. Computational fragment-based drug discovery (FBDD) represents apowerful 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 new compounds generated were assessed by benchmark dataset verification, docking studies, and QS AR model simulation. Subsequently, the structurally diverse compounds, with reported or unreported scaffolds, can be observed from the top 20 in silico design/synthesized compounds, which were predicted to be potential mGlu5 allosteric modulators. The in silico designed compounds with reported scaffolds may fill SAR holes in the known, patented series of mGlu5 modulators . And the generation of compounds without reported activities 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 and synthesis in the future.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Bian, Yueminyub12@pitt.eduyub120000-0002-5845-772X
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMcDermott, Leelam179@pitt.edulam179
Committee MemberYang, Pengpey12@pitt.edupey12
Thesis AdvisorXie, Xiang-Qunxix15@pitt.eduxix15
Date: 1 May 2017
Date Type: Publication
Defense Date: 30 March 2017
Approval Date: 1 May 2017
Submission Date: 7 April 2017
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 92
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Allosteric modulator, Computational fragment-based drug discovery, Metabotropic glutamate receptor 5, GPCRs
Date Deposited: 01 May 2017 12:04
Last Modified: 01 May 2018 05:15


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