T321:jaramillo:Evaluation of Orthogonal Compound Mixture Sets for High Throughput Screening

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Angela M. Jaramillo1; Laszlo Kiss2, Bradley P. Feuston3; Ansu Bagchi4; Robert A. Liehr1; Edward M. Hudak1; Carissa Quinn1

Exploratory and Translational Sciences 1, External Discovery and Preclinical Sciences2, Chemistry Modeling and Informatics3, Informatics IT4, Merck & Company, North Wales, PA

Ion channels represent an attractive group of targets for drug discovery. They play a role in a variety of physiological processes and are implicated in an assortment of disorders. Despite the advances of fluorescent membrane potential dyes and automated patch clamp technologies, these targets continue to be an under-exploited target class. This is partly due to the labor-intensive nature of the gold standard assay of patch-clamp electrophysiology. In an effort to expand the number of compounds that can be tested in an electrophysiology assay, we explored the use of orthogonal compound mixtures sets. Orthogonal mixtures provide a self-convoluting matrix which significantly reduces screening time and reagent costs while extending the number of compounds tested in a given time on a lower throughput platform. We chose to evaluate an orthogonal pooling strategy that had 10 compounds per well with three mixture sets (O=3). In an effort to understand the effectiveness of the mixtures, we studied an ion channel using population patch clamp-based assay on the IonWorks Quattro. Complementary to the screening, a mathematical optimization algorithm was developed to enable identification of probable hits from the complex assay data. The evaluation of this assay against the orthogonal mixtures provided a successful starting point into investigating the expansive uses of mixture sets with high throughput screening.

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