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May 15, 2010 (Vol. 30, No. 10)

Pioneering New Collaborative Approaches

NIH Chemical Genomics Center Utilizes a Broad and Diverse Range of Technologies

  • Click Image To Enlarge +
    NCGC’s ability to perform concentration response-based screening or quantitative high-throughput screening is enabled by Kalypsys robotics. Here, Drs. James Inglese and Natasha Thorne examine three Staubli anthropomorphic arms and a 1,536-well plate gripper.

    Following completion of the Human Genome Project (HGP) in 2004, the scientific community moved to apply this knowledge to gain a better understanding of human disease. Specifically, the analysis of small molecules offered a unique opportunity toward the development of therapeutics.

    To investigate this new area of science, the NIH Chemical Genomics Center (NCGC) was established, effectively creating a disease-research extension of the HGP. From an organizational standpoint, the center is unique in its focus on shared knowledge. The vehicle for disseminating much of this information is PubChem. Through this database, the discoveries at the center serve as major resources.

    Additionally, the NCGC, intramural NIH project scientists, and extramural investigators maintain a close collaboration through a molecular libraries probe production centers network (MLPCN). In addition to the direct deposition of data generated from MLPCN projects into the PubChem database, members of the network and their extramural collaborators often publish the findings resulting from small molecule screening and probe optimization as more in depth studies in scientific journals.

    The MLPCN’s small molecule repository contains over 350,000 compounds that are used for small molecule screening across the network of centers. Resource allocation, flexibility in data handling, and timely turnaround for test results all facilitate the communicative efforts between the institutions operating in the network.

    NCGC uses various technologies and methods for small molecule assay development, quantitative high-throughput screening (HTS), cheminformatics, and chemistry. Using these techniques, the NCGC aims to elucidate an efficient pathway to small molecule probe discovery, the applications of which can include therapeutic discovery.

    The main activities of the center focus on screening molecular targets and cellular phenotypes, chemical optimization of verified chemotypes, and expanding technologies enabling chemical biology, including siRNA screening. While there are specific goals based on researching particular diseases and biological pathways, the programs that involve general signaling pathways, for example, apply broadly and allow for the expansion of high-throughout screening technologies across disease categories.

    Outside of basic research, the center partakes in studies on cancer and infectious diseases of the developing world, including malaria, schistosomiasis, and trypanosomiasis. Through the center’s partnership with the NIEHS and EPA, an investigation of in vitro systems toxicology has also been under way.

    The NCGC’s use of HTS, which permits both target-driven and phenotype-driven drug discovery, has enabled the examination of diverse biological responses of large numbers of chemical substances. The main function of the technology is to promote “rapid testing,” according to Doug Auld, Ph.D., group leader for genomic assay technologies, and James Inglese, Ph.D., deputy director of the NCGC.

    Projects involve screening the compound library using high-quality assays, often designed with input from the NCGC, on robotically enabled platforms; the results of the screens are then analyzed using informatics procedures developed at NCGC. To maximize output for the variety of chemical compounds as dose-response relationships, practices such as the reduction of reagents through assay miniaturization and quality control  through reagent stability and assay variability testing have proved beneficial.

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