title: Iterative experimental and virtual high-throughput screening identifies metabotropic glutamate receptor subtype 4 positive allosteric modulators.
abstract: Activation of metabotropic glutamate receptor subtype 4 has been shown to be efficacious in rodent models of Parkinson's disease. Artificial neural networks were trained based on a recently reported high throughput screen which identified 434 positive allosteric modulators of metabotropic glutamate receptor subtype 4 out of a set of approximately 155,000 compounds. A jury system containing three artificial neural networks achieved a theoretical enrichment of 15.4 when selecting the top 2 % compounds of an independent test dataset. The model was used to screen an external commercial database of approximately 450,000 drug-like compounds. 1,100 predicted active small molecules were tested experimentally using two distinct assays of mGlu(4) activity. This experiment yielded 67 positive allosteric modulators of metabotropic glutamate receptor subtype 4 that confirmed in both experimental systems. Compared to the 0.3 % active compounds in the primary screen, this constituted an enrichment of 22 fold.
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN, 37232-6600, USA.
authors.forename: Ralf
authors.initials: R
authors.lastname: Mueller
authors.forename: Eric S
authors.initials: ES
authors.lastname: Dawson
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.forename: Mariusz
authors.initials: M
authors.lastname: Butkiewicz
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Jens
authors.initials: J
authors.lastname: Meiler
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001583:Benzoxazoles / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D016571:Neural Networks, Computer; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D014584:User-Computer Interface
chemical_list: D001583:Benzoxazoles; D018094:Receptors, Metabotropic Glutamate; D054852:Small Molecule Libraries; C108823:metabotropic glutamate receptor 4