Analysis of Iterative Screening with Stepwise Compound Selection Based on Novartis in-house HTS DataReport as inadecuate


Analysis of Iterative Screening with Stepwise Compound Selection Based on Novartis in-house HTS Data


Analysis of Iterative Screening with Stepwise Compound Selection Based on Novartis in-house HTS Data - Download this document for free, or read online. Document in PDF available to download.

Publication Date: 2016-02-16

Journal Title: ACS Chemical Biology

Publisher: ACS Publications

Volume: 11

Issue: 5

Pages: 1255-1264

Language: English

Type: Article

Metadata: Show full item record

Citation: Paricharak, S., IJzerman, A. P., Bender, A., & Nigsch, F. (2016). Analysis of Iterative Screening with Stepwise Compound Selection Based on Novartis in-house HTS Data. ACS Chemical Biology, 11 (5), 1255-1264.

Description: This is the author accepted manuscript. The final version is available from ACS Publications via http://dx.doi.org/10.1021/acschembio.6b00029

Abstract: ABSTRACT With increased automation and larger compound collections, the development of high-throughput screening (HTS) started replacing previous approaches in drug discovery from around the 1980s onwards. However, even today it is not always appropriate, or even feasible, to screen large collections of compounds in a particular assay. Here, we present an efficient method for iterative screening of small subsets of compound libraries. With this method the retrieval of active compounds is optimized using their structural information and biological activity fingerprints. We validated this approach retrospectively on 34 Novartis in-house HTS assays covering a wide range of assay biology, including cell proliferation, antibacterial activity, gene expression and phosphorylation. This method was employed to retrieve subsets of compounds for screening, where selected hits from any given round of screening were used as starting points to select chemically and biologically similar compounds for the next iteration. By only screening ~1% of the full screening collection (~15,000 compounds), the method consistently retrieves diverse compounds belonging to the top 0.5% most active compounds for the HTS campaign. For most of the assays over half of the compounds selected by the method were found to be among the 5% most active compounds of the corresponding full-deck HTS. In addition, the stringency of the iterative method can be modified depending on the number of compounds one can afford to screen, making it a flexible tool to discover active compounds efficiently.

Keywords: HTS screening, iterative screening, in silico heuristic compound selection

Sponsorship: S. Paricharak thanks the Netherlands Organisation for Scientific Research (NWO, grant number NWO-017.009-065), Novartis Institutes for BioMedical Research (NIBR) and the Prins Bernhard Cultuurfonds for funding and C. Parker, M. Frederiksen, G. Landrum and N. Fechner for insightful discussions.

Identifiers:

This record's URL: http://dx.doi.org/10.1021/acschembio.6b00029https://www.repository.cam.ac.uk/handle/1810/253845





Author: Paricharak, ShardulIJzerman, Adriaan P.Bender, AndreasNigsch, Florian

Source: https://www.repository.cam.ac.uk/handle/1810/253845



DOWNLOAD PDF




Related documents