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"Plate cherry picking": a novel semi-sequential screening paradigm for cheaper, faster, information-rich compound selection.

Crisman, Thomas and Jenkins, Jeremy and Parker, Christian and Hill, William and Bender, Andreas and Deng, Zhan and Nettles Jr., James and Davies, John and Glick, Meir (2007) "Plate cherry picking": a novel semi-sequential screening paradigm for cheaper, faster, information-rich compound selection. Journal of Biomolecular Screening : the official journal of the Society for Biomolecular Screening, 12 (3). pp. 320-327. ISSN 1087-0571

Abstract

This work describes a novel semi-sequential technique for in silico enhancement of high-throughput screening (HTS) experiments now employed at Novartis. It is used in situations in which the size of the screen is limited by the readout (e.g., high-content screens) or the amount of reagents or tools (proteins or cells) available. By performing computational chemical diversity selection on a per plate basis (instead of a per compound basis), 25% of the 1,000,000-compound screening was optimized for general initial HTS. Statistical models are then generated from target-specific primary results (percentage inhibition data) to drive the cherry picking and testing from the entire collection. Using retrospective analysis of 11 HTS campaigns, the authors show that this method would have captured on average two thirds of the active compounds (IC(50) < 10 microM) and three fourths of the active Murcko scaffolds while decreasing screening expenditure by nearly 75%. This result is true for a wide variety of targets, including G-protein-coupled receptors, chemokine receptors, kinases, metalloproteinases, pathway screens, and protein-protein interactions. Unlike time-consuming "classic" sequential approaches that require multiple iterations of cherry picking, testing, and building statistical models, here individual compounds are cherry picked just once, based directly on primary screening data. Strikingly, the authors demonstrate that models built from primary data are as robust as models built from IC(50) data. This is true for all HTS campaigns analyzed, which represent a wide variety of target classes and assay types.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: cherry picking; high-throughput screening; semi-sequential screening; plate diversity approach
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Date Deposited: 14 Dec 2009 14:00
Last Modified: 31 Jan 2013 01:17
URI: https://oak.novartis.com/id/eprint/439

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