title: An informatic pipeline for managing high-throughput screening experiments and analyzing data from stereochemically diverse libraries.
abstract: Integration of flexible data-analysis tools with cheminformatics methods is a prerequisite for successful identification and validation of "hits" in high-throughput screening (HTS) campaigns. We have designed, developed, and implemented a suite of robust yet flexible cheminformatics tools to support HTS activities at the Broad Institute, three of which are described herein. The "hit-calling" tool allows a researcher to set a hit threshold that can be varied during downstream analysis. The results from the hit-calling exercise are reported to a database for record keeping and further data analysis. The "cherry-picking" tool enables creation of an optimized list of hits for confirmatory and follow-up assays from an HTS hit list. This tool allows filtering by computed chemical property and by substructure. In addition, similarity searches can be performed on hits of interest and sets of related compounds can be selected. The third tool, an "S/SAR viewer," has been designed specifically for the Broad Institute's diversity-oriented synthesis (DOS) collection. The compounds in this collection are rich in chiral centers and the full complement of all possible stereoisomers of a given compound are present in the collection. The S/SAR viewer allows rapid identification of both structure/activity relationships and stereo-structure/activity relationships present in HTS data from the DOS collection. Together, these tools enable the prioritization and analysis of hits from diverse compound collections, and enable informed decisions for follow-up biology and chemistry efforts.
authors.affiliation: Chemical Biology Platform, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. carolm@broadinstitute.org
authors.forename: Carol A
authors.initials: CA
authors.lastname: Mulrooney
authors.forename: David L
authors.initials: DL
authors.lastname: Lahr
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Quintin
authors.forename: Willmen
authors.initials: W
authors.lastname: Youngsaye
authors.forename: Dennis
authors.initials: D
authors.lastname: Moccia
authors.forename: Jacob K
authors.initials: JK
authors.lastname: Asiedu
authors.forename: Evan L
authors.initials: EL
authors.lastname: Mulligan
authors.forename: Lakshmi B
authors.initials: LB
authors.lastname: Akella
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Marcaurelle
authors.forename: Philip
authors.initials: P
authors.lastname: Montgomery
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bittker
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.forename: Stephen
authors.initials: S
authors.lastname: Brudz
authors.forename: Sivaraman
authors.initials: S
authors.lastname: Dandapani
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Duvall
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Tolliday
authors.forename: Andrea
authors.initials: A
authors.lastname: De Souza
mesh_terms: D000465:Algorithms; D020650:Combinatorial Chemistry Techniques; D016208:Databases, Factual; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006801:Humans; D013329:Structure-Activity Relationship