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.

Novel tricyclic glycal-basedTRIB1inducers that reprogram LDL metabolism in hepatic cells

“…From the initial 'sparse matrix' 12 designed tricyclic glycal library, 10 SAR was observed in the HTS at both R 1 and R 2 appendage sites, visualized in Fig. 1A, 13 but the trifluoromethyl phenyl amide and indane motifs were superior at the respective positions. BRD8518 was characterized further and showed improved potency in inhibiting ApoB secretion, indicating inhibition of VLDL secretion, as predicted based on known effect of TRIB1 overexpression on inhibition of lipogenesis 7 (Fig.…”

Target-Based Identification of Whole-Cell Active Inhibitors of Biotin Biosynthesis in Mycobacterium tuberculosis

“…Cheminformatic analysis followed by manual culling of the 298 confirmed hits suggested chemical clustering into 65 groups of which 34 groups were defined by multiple examples sharing a common scaffold (Table S1) (Mulrooney, et al, 2013). Tetrahydroisoquinoline 10 , from a DOS library and shown in Table 1, is the most abundant scaffold (36 analogs) representing nearly 12% of all hits and including the most potent hit identified with an IC 50 value of 75 nM.…”

Development and Validation of a Novel Leishmania donovani Screening Cascade for High-Throughput Screening Using a Novel Axenic Assay with High Predictivity of Leishmanicidal Intracellular Activity

“…These libraries were prepared as part of a collection of skeletally diverse azetidine-based scaffolds. An important feature of this compound collection is that it contains stereochemical diversity and in our experience, Stereochemical Structure Activity (SSAR) analysis of a hit compound can give an indication on how selective and specific its interaction is with its molecular target [ 45 ]. While two stereoisomers of BRD6650 were active, the majority of the stereoisomers tested had at least a 9-fold drop in potency indicating a selective and specific interaction with a molecular target.…”