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J Comput Aided Mol Des DOI:10.1007/s10822-013-9641-y

An informatic pipeline for managing high-throughput screening experiments and analyzing data from stereochemically diverse libraries.

Publication TypeJournal Article
Year of Publication2013
AuthorsMulrooney, CA, Lahr, DL, Quintin, MJ, Youngsaye, W, Moccia, D, Asiedu, JK, Mulligan, EL, Akella, LB, Marcaurelle, LA, Montgomery, P, Bittker, JA, Clemons, PA, Brudz, S, Dandapani, S, Duvall, JR, Tolliday, NJ, de Souza, A
JournalJ Comput Aided Mol Des
Date Published2013 May
KeywordsAlgorithms, Combinatorial Chemistry Techniques, Databases, Factual, Drug Design, High-Throughput Screening Assays, Humans, Structure-Activity Relationship

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.


Alternate JournalJ. Comput. Aided Mol. Des.
PubMed ID23585218
PubMed Central IDPMC5554947
Grant ListU54RL1CA133834 / CA / NCI NIH HHS / United States
UL1DE019585 / DE / NIDCR NIH HHS / United States
RL1HG004671 / HG / NHGRI NIH HHS / United States
U54 HG005032 / HG / NHGRI NIH HHS / United States
UL1 DE019585 / DE / NIDCR NIH HHS / United States
RL1GM084437 / GM / NIGMS NIH HHS / United States
1U54HG005032-1 / HG / NHGRI NIH HHS / United States
P50 GM069721 / GM / NIGMS NIH HHS / United States
RL1 GM084437 / GM / NIGMS NIH HHS / United States
P50GM069721 / GM / NIGMS NIH HHS / United States
RL1 HG004671 / HG / NHGRI NIH HHS / United States
RL1 CA133834 / CA / NCI NIH HHS / United States