The Pilot Phase of the NIH Chemical Genomics Center

Abstract

The NIH Chemical Genomics Center (NCGC) was the inaugural center of the Molecular Libraries and Screening Center Network (MLSCN). Along with the nine other research centers of the MLSCN, the NCGC was established with a primary goal of bringing industrial technology and experience to empower the scientific community with small molecule compounds for use in their research. We intend this review to serve as 1) an introduction to the NCGC standard operating procedures, 2) an overview of several of the lessons learned during the pilot phase and 3) a review of several of the innovative discoveries reported during the pilot phase of the MLSCN. High-throughput screening at the NCGCHigh-throughput screening (HTS) is one of the most established mechanisms to identify small molecules with biological activity [1]. The model of the Molecular Libraries and Screening Center Network (MLSCN) provides researchers that have established assays for either isolated targets or cellular phenotypes the resources to conduct a HTS for small molecules that affect that target or phenotype [2]. HTS has evolved to address a wide-range of biological functions by employing a multitude of formats that now includes assays for purified proteins and enzymes as well as cell-based assays for signal transduction pathways, protein complex formation, transcriptional regulation of gene function, pre-mRNA splicing events, and epigenetics [3]. The NIH Chemical Genomics Center (NCGC) has established a number of innovations aimed at reducing the burden of false positives (FP) and false negatives (FN) associated with HTS as well as providing efficient use of assay reagents and compound samples. Primary among these innovations is the establishment of multi-concentration HTS using miniaturized assay volumes (<10 μL/well) in 1536-well microtiter plates, referred to as quantitative high-throughput screening (qHTS) [4]. qHTS is capable of screening small molecules at multiple concentrations (typically between 7 and 15 specified concentrations) based upon the built-in flexibility of inter-plate titrations (Fig. 1). By miniaturizing to a 1536 well-plate format the qHTS process essentially provides cost-effective high-throughput pharmacology by delivering concentration response curves (CRCs) for each library member. The benefits of qHTS include reducing FP and capturing FN, allowing the data to be mined to determine a compound's pharmacological profile, the ability to identify assay related artifacts, and the ability to construct structure activity relationships (SAR) from the primary screening data to drive probe optimization immediately after completion of the screen. The NCGC has applied qHTS to many different assay formats * Corresponding authors: craigt@nhgri.nih.gov, austinc@mail.nih.gov. Send proofs to: Dr. Craig J. Thomas, NIH Chemical Genomics Center, NHGRI, National Institutes of Health, 9800 Medical Center Drive, Building B, Room 3005, MSC: 3370, Bethesda, MD 20892-3370 NIH Public Access Author ManuscriptCurr Top Med Chem. Author manuscript; ava...

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