Selective potentiators of the metabotropic glutamate receptor subtype mGluR5 have exciting potential for development of novel treatment strategies for schizophrenia and other disorders that disrupt cognitive func-tion. The latest generation of selective mGluR5 potentiators is based on the lead compound CDPPB and features systemically active compounds with long half-lives that cross the blood-brain barrier. A high-throughput screen (HTS) for mGluR5 potentiators at Vanderbilt's screening center revealed a large and diverse set of about 1400 substances (1% hit rate) whose activity was validated in independent experiments. A previous exploratory research grant """"""""Novel Schizophrenia Therapeutics by Virtual High-Throughput Screening"""""""" (R21 MH082254) enabled testing of 813 compounds predicted through cheminformatics. 252 of these compounds were confirmed as active PAMs equaling an enrichment of >30 when compared with the original screen. The present proposal seeks to leverage these proof-of-principle results for the development of a tailored cheminformatics framework for drug discovery of allosteric modulators of brain GPCRs, apply these tools to inform an existing therapeutic discovery program of mGluR5 potentiators at Vanderbilt University, and disseminate the methods broadly through the NIH molecular libraries program. The central hypothesis of this proposal is that the complex relationship between chemical structure and biological activity of mGluR5 potentiators observed in this HTS can be used to generate a pharmacophore of the mGluR5 allosteric site. This map of steric and electronic features necessary for optimal interaction of modulators with mGluR5 will not only inform our understanding of the allosteric modulation of brain GPCRs. The methods proposed overcome limitations of present cheminformatics techniques by enabling identification of novel chemotypes through virtual screening (scaffold hoping), and allowing design of focused libraries in hit-to- lead optimization of novel schizophrenia therapeutics. The generalizbility of the approach will be tested through application on negative modulators of mGluR5, a potential novel treatment strategy of fragile X syndrome, a CNS disorder associated with autism spectrum disorders (ASD) among multiple other symptoms. The developed applications will be made freely and readily accessible for academic research. The employed QSAR models require no crystal structure of the target brain GPCR. Hence the method can be readily applied to membrane proteins-such as GPCRs-which are target of 40-50% of modern medicinal drugs.
Ligands for specific mGluR subtypes have potential for treatment of a wide variety of neurological and psychiatric disorders. We will use computational methods identify potentiators of mGluR5, compounds that have exciting potential as treatment strategy for schizophrenia. In silico hit compounds will be experimentally validated and enter hit-to-lead optimization.
|Butkiewicz, Mariusz; Wang, Yanli; Bryant, Stephen H et al. (2017) High-Throughput Screening Assay Datasets from the PubChem Database. Chem Inform 3:|
|Krug, Ulrike; Alexander, Nathan S; Stein, Richard A et al. (2016) Characterization of the Domain Orientations of E. coli 5'-Nucleotidase by Fitting an Ensemble of Conformers to DEER Distance Distributions. Structure 24:43-56|
|Li, Bian; Mendenhall, Jeffrey; Nguyen, Elizabeth Dong et al. (2016) Accurate Prediction of Contact Numbers for Multi-Spanning Helical Membrane Proteins. J Chem Inf Model 56:423-34|
|Moretti, Rocco; Bender, Brian J; Allison, Brittany et al. (2016) Rosetta and the Design of Ligand Binding Sites. Methods Mol Biol 1414:47-62|
|Donahue, John P; Levinson, Rebecca T; Sheehan, Jonathan H et al. (2015) Genetic analysis of the localization of APOBEC3F to human immunodeficiency virus type 1 virion cores. J Virol 89:2415-24|
|Putnam, Daniel K; Weiner, Brian E; Woetzel, Nils et al. (2015) BCL::SAXS: GPU accelerated Debye method for computation of small angle X-ray scattering profiles. Proteins 83:1500-12|
|Kothiwale, Sandeepkumar; Borza, Corina M; Lowe Jr, Edward W et al. (2015) Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery. Drug Discov Today 20:255-61|
|Alexander, Nathan S; Preininger, Anita M; Kaya, Ali I et al. (2014) Energetic analysis of the rhodopsin-G-protein complex links the ?5 helix to GDP release. Nat Struct Mol Biol 21:56-63|
|Weiner, Brian E; Alexander, Nathan; Akin, Louesa R et al. (2014) BCL::Fold--protein topology determination from limited NMR restraints. Proteins 82:587-95|
|Pedragosa-Badia, Xavier; Sliwoski, Gregory R; Dong Nguyen, Elizabeth et al. (2014) Pancreatic polypeptide is recognized by two hydrophobic domains of the human Y4 receptor binding pocket. J Biol Chem 289:5846-59|
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