Iterative experimental and virtual high-throughput screening identifies metabotropic glutamate receptor subtype 4 positive allosteric modulators.

Mueller R, Dawson ES, Niswender CM, Butkiewicz M, Hopkins CR, Weaver CD, Lindsley CW, Conn PJ, Meiler J
J Mol Model. 2012 18 (9): 4437-46

PMID: 22592386 · PMCID: PMC3766737 · DOI:10.1007/s00894-012-1441-0

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.

MeSH Terms (13)

Allosteric Regulation Animals Benzoxazoles High-Throughput Screening Assays Humans Models, Molecular Neural Networks (Computer) Quantitative Structure-Activity Relationship Rats Receptors, Metabotropic Glutamate ROC Curve Small Molecule Libraries User-Computer Interface

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