The NIH Chemical Genomics Center (NCGC)

The NIH Chemical Genomics Center (NCGC) is an ultrahigh-throughput screening center of the Molecular Libraries Probe Production Centers Network (MLPCN) that generates chemical probes to understand molecular and cellular functions and serve as starting points for drug development, particularly for rare and orphan diseases. Collaborating with an enormous diversity of biomedical researchers worldwide, the NCGC brings a biopharmaceutical approach to academic chemical biology, using state-of-the-art assay technologies, fully automated robotic screening, a unique screening paradigm and informatics platform, and high-throughput parallel synthetic and analytical chemistry to discover and develop probe compounds that define novel biology. The NCGC has a particular focus on developing chemical probes for currently “non-druggable” targets and pathways, and developing new paradigms for HTS, informatics, and chemistry to make probe development more efficient. NCGC’s titration-based quantitative HTS (qHTS) paradigm enables the comprehensive profiling of the biological activities and physiochemical properties of large chemical compound libraries. The long-term goal of the NCGC is to discover general principles by which small molecules and their targets interact, delineate gene/protein functions and their relationships based on small molecule interactions, and catalyze the development of new drugs for human disease by making both its data and its chemical probes available to the research community without restriction.

The MLPCN is a consortium of HTS centers that perform biological assays submitted by the research community against the Molecular Libraries Small Molecule Repository, and perform optimization chemistry on the actives to produce chemical probes. All of the results from the MLPCN’s activities are placed into a public database called PubChem, and information about chemical probes is being made available to all researchers, in both public and private sectors, for their use in studying biology and disease.

Informatics at the NCGC include: hardware and software solutions for assay design, qHTS analysis, computational chemistry, modeling and compound management, novel algorithm and tool development, integral part of project teams, close collaboration with biologists and chemists, and “build, buy, and integrate” approach to analysis systems.

NCGC’s HTS is fully automated on several stateof-the-art automation platforms, the Kalypsys and High Resolution Biology systems and includes a variety of reagent dispensing/handling devices and detectors, including: Kalypsys multichannel cell and reagent dispenser/aspirators, Dual-Kalypsys 1536-pin compound delivery systems, Aurora BioRAPTR FRD, Aurora PicoRAPTR, PE Evolution, CyBio Cybi-well and Cybi-disk TTP LabTech Acumen eX3 Explorers, GE/Amersham InCell 1000, PerkinElmer ViewLux, Tecan Safire Plate Reader, and PerkinElmer EnVision.

Chemistry at NCGC is build upon enthusiastic collaboration between all departments fostered by the project team paradigm. Academic freedom coupled with industry resources and experience means:

Frequent interaction with scientific community, including leaders in academia and industry, access to the vast resources of the NIH, and open opportunities for publication and creativity
Dedicated and dynamic informatics resources for efficient data analysis and visualization
Dedicated analytical resources to ensure the highest quality of compound data
Latest tools available for efficient parallel synthesis and strong support from engineering to automate and streamline processes

NIH Chemical Genomics Center Capabilities

Assay Formats	Screening Capabilities	Biological Expertise
Absorbance	1536-well plates; HTS (primary) and secondary screens	Enzyme assays (kinase, phosphatase, protease, etc.)
AlphaScreen	1536-well plates; HTS (primary) and secondary screens	Protein-protein interaction, replacement of ELISA assay, protein-peptide interaction
Fluorescence Intensity	1536-well plates; HTS (primary) and secondary screens	Enzyme assays (kinase, phosphatase, protease, betalactamase reporter, etc.); Receptor binding assay
Fluorescence Polarization	1536-well plates; HTS (primary) and secondary screens	Protein-peptide interaction, protein-DNA/RNA interaction, kinase assay (IMAP)
Time Resolved Fluorescence	1536-well plates; HTS (primary) and secondary screens	Redox enzyme systems
HTRF/LANCE (FRET)	1536-well plates; HTS (primary) and secondary screens	cAMP assay, Kinase assay
Luminescence	1536-well plates; HTS (primary) and secondary screens	Enzyme assays, luciferase reporter-gene assay, cytotoxicity/ cell growth assay (ATP content)
Laser scanning cytometry (Acumen Explorer)	1536-well plates; HTS (primary) and secondary screens	GFP assay, nuclear translocation assay
Microscopy-based imaging (INCell 1000)	1536-well plates; secondary screen	GFP-based assays, antibody/dye staining assays
FDSS-7000 Kinetic Reader	1536-well plates; HTS (primary) and secondary screens	Intracellular calcium kinetic assay (GPCRs and calcium channels), ion flex assay (ion channels), aequorin assay (GPCRs)
Real-time cell analyzer (Acea’s impedance-based platform)	16-well strip/96-well plate; secondary kinetic assay	Cell growth rate, cytotoxicity kinetic measurement BLS-2 level assays for infectious diseases

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