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U.S. National Institutes of Health
Last Updated: 11/08/11
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Emory Chemical Biology Discovery Center

Emory University

Mission

Our mission is to discover novel chemical leads targeted to disease-related proteins for research tools and therapeutics, and to train the next generation of drug discovery scientists.

The Emory Chemical Biology Discovery Center (ECBDC) was created in 2003 to enhance Emory’s capabilities in small molecule drug discovery and development. Subsequently, through its role as a node in the NIH MLSCN and as a collaborator in numerous Emory projects, the ECBDC has built a powerful infrastructure for high-throughput small molecule screening and subsequent hit optimization via medicinal chemistry. The ECBDC offers state-of-the-art HTS and HCS capabilities with multiple integrated robotic systems and has access to a collection of small molecule compound libraries. These capabilities are complemented by our expertise in assay development, HTS, HCS, screeninformatics, cheminformatics, and medicinal chemistry. The ECBDC’s assay and screening expertise spans from conventional biochemical and cell-based assays and screens to state-of-the-art multiplexed assays, phenotypic imaging screening, and label-free pathway signature-based screens, including complex multiplexing protein-protein interaction screens with our information-rich HTS platform (iHTS). The ECBDC leverages its high throughput expertise for functional genomics studies, specifically focused on the identification and interrogation of therapeutically important protein-protein interactions. With established infrastructure, the ECBDC provides expertise and support to drive mechanism-driven screens and hit identifications for innovative cancer agent discovery.

Organization

The ECBDC is organized around the following three functions: Assay Development and Implementation, High-Throughput Screening, and Informatics. The ECBDC is anchored by investigators within the Winship Cancer Institute of Emory University and is functionally integrated with the drug discovery and development capabilities of the Emory Institute for Drug Discovery (EIDD). Through these partnerships, the ECBDC has access to additional resources including target identification and validation, animal models (Winship Cancer Institute), as well as medicinal chemistry and ADME/PK analysis (EIDD), which enhance the ECBDC’s ability to fulfill CBC directives.

EMORY CHEMICAL BIOLOGY DISCOVERY CENTER Organization

Assay Capabilities

The primary objectives of the Assay Program are to develop bioassays for valuable targets that can be efficiently adapted for HTS/uHTS or HCS operations, and to develop biologically relevant secondary assays for hit confirmation and optimization. To perform a wide variety of bioassays, the ECBDC has assembled multiple, independent parallel robotic systems for HTS/uHTS/iHTS and HCS operations that are capable of handling 96-, 384-, and 1536-well plate formats. These systems accommodate many different assay formats and are particularly well-suited for conventional and multiplex protein-protein interactions and phenotypic screens. The ECBDC has developed a unique information-rich HTS format, termed iHTS, which monitors the interaction of one protein with multiple partners with the recognition that protein interactions often occur in a multiprotein complex. The ECBDC screening platforms include:

  • HTS/HCS System I: Features a central vertical robotic system with three outpost readers: (i) EnVision multimode reader (HTS in 96/384/1536 well format), (ii) FlexStation II agonist-injectable, 384-well fluorescence reader, and (iii) ImageXpress (HCS in 96/384well format). This system is integrated with a cell hotel, plate stacker, and various liquid handlers equipped with pin tools for low-volume (nL) transfer. All of these components are in an enclosed environment, facilitating live-cell HCS screens under aseptic conditions.

  • HTS/HCS System II: Features the Twister II robot integrated with (i) an EnVision multimode reader (HTS in 96/384/1536-well format) and (ii) ImageXpress (HCS in 96/384/1536 well format) supported by the Sciclone liquid handling workstation.

  • HTS System III: Features Corning’s Epic system for label-free molecular interaction screens for hit identification and confirmation by direct detection of protein-compound binding and cell-based screens under physiological conditions.

Using these systems, the ECBDC can perform a wide variety of bioassays. Some examples of ECBDC assay capabilities include:

  • Macromolecular interactions (FP, TR-FRET, AlphaScreen):
    • Protein-protein interactions
    • Protein-RNA interactions
    • Multiplexed protein-protein interactions
  • Cellular signaling pathway assays
    • Dynamic mass redistribution assay for pathway analysis (label-free optical biosensor)
    • Cell based cAMP/GPCR pathway assay (TR-FRET)
  • Reporter assays (luminescence, fluorescence)
    • Functional reporters (e.g. protein folding)
    • Transcriptional reporters (cell-based HTS)
  • HCS assays (automated imagers)
    • Subcellular redistribution assays
    • Morphological change assays
    • Whole organism imaging
  • Cell viability and apoptosis (absorbance, FI, imager)
  • Soft agar assay for anchorage-independent cell growth (FI, 384-well)
  • Biochemical assays, including enzyme kinetics assay for enzyme modulators (FI, TR-FRET)
  • Viral infection assays (cell-based FI, automated imager)

Additional established assays for secondary screens include various protein-protein interaction assays, such as protein pull-down assays, cytoblots, Western blots, ELISA, two-hybrid assays, and protein complementation assays. Oncology-related assays include cytotoxicity, cell proliferation, apoptosis (e.g., Annexin V staining, caspase activation, mitochondrial depolarization), cell cycle analysis, tumorigenesis, cell migration, and cell invasion assays.

Quality Control

The Agilent 6100 Series Quadrupole LC/MS is used for hit compound screening and molecular weight confirmation. The HTS team also executes quality control procedures (LC-MS, NMR, elemental analysis) on each confirmed hit that passes secondary screens to ensure the transfer of high quality hit compounds to the next phase of the project. To prevent unnecessary efforts around an impure compound, the structure and purity of hit compounds are confirmed using LC/MS, NMR, and elemental analysis when appropriate.

Informatics Capacities

The CambridgeSoft Enterprise software serves as the backbone of the informatics environment at the center. It provides an integrated method of analyzing HTS/HCS assay results. Tools such as Inventory Loader, Inventory Manager, BioAssay HTS, and BioSAR are used for consolidating assay results into a central database for analysis and mining. The CambridgeSoft system consists of a CambridgeSoft Web Server that contains the Inventory Manager and BioSAR tools, an Oracle database, and a proxy server that provides network connectivity of tools such as Inventory Loader, BioAssay HTS, ChemFinder, and ChemDraw. The ECBDC utilizes custom in-house software for project management (Labview), and supplements HTS/HCS capabilities and expertise with predictive calculations including 2D clustering, protein-ligand molecular modeling, receptor and ligand-based virtual screening, and ADME/Tox calculations. Information derived from these calculations is used to aid medicinal chemistry efforts to choose a lead from primary HTS hits and guide synthetic optimization of the selected lead compounds. The molecular modeling software tools used include LeadScope, Pipeline Pilot, Glide, and QikPro.

 

ECBDC Anchoring Institutes

Animal models and novel cancer target discovery

We have access to cancer animal models for compound testing, which include both animal imaging and conventional xenograft tumor models through our integrated interactions with programs at the Winship Cancer Institute. Animal tumor models include lung cancer, breast cancer, prostate cancer, and head and neck cancer models. The Winship Cancer Institute is a matrix organization that promotes and supports interactions among a diverse group of individuals from various Emory units and departments. The Winship Cancer Institute is organized into four interdisciplinary research programs: Cancer Genetics and Epigenetics, Cancer Cell Biology, Discovery and Developmental Therapeutics, and Cancer Prevention and Control. Seven shared resources support research across the continuum from basic to translational to clinical to population sciences. The Winship Cancer Institute provides depth of cancer biology for target discovery, mechanism-driven assay development for HTS and HCS, and various tumorigenesis assays for drug discovery, e.g., imaging with animal tumor models.

Preclinical drug discovery capabilities through the Emory Institute for Drug Discovery (EIDD)

The EIDD was founded to provide an organization to carry out hit-to-lead medicinal chemistry research and preclinical development. The EIDD is staffed with recognized leaders in the drug discovery arena and has extensive capabilities to perform hit-to-lead medicinal chemistry, PK profiling, in vivo pharmacology, and early in vitro and in vivo toxicology studies. It has medium-throughput capability for ADME/Tox and has developed sensitive and selective bioanalytical assay methodologies using a state-of-the-art LC/MS/MS system (Applied Biosystems/MDS SCIEX 3000 and 4000 Q TRAP LC/MS/MS Systems) for the determination of analog plasma levels and the identification and characterization of metabolites. The EIDD will work closely with the ECBDC in support of the NCI CBC to provide medicinal chemistry perspective for hit selection and medicinal chemistry capabilities for hit optimization to promote the identification of lead compounds for cancer drug discovery.

Website:

http://www.pharm.emory.edu/ECBDC/

Contact:

Margaret A. Johns, PhD
Administrative Officer/Project Manager
emory-ncicbc@pharm.emory.edu

Haian Fu, PhD
Director
hfu@emory.edu