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Lead Identification

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Drug Discovery
Lead Identification Department

As a discipline, high throughput screening (HTS) employs sophisticated automation, detection & assay technologies to test large (several hundred thousand member) compound collections for biological or biochemical activity. HTS operations are typically implemented by large pharmaceutical companies to aid their drug discovery research efforts. Through funding from the State of Florida and Palm Beach County, Scripps has been given the opportunity to create a state-of-the art HTS operation at the Scripps Florida campus. The operation is being constructed and staffed by the Lead ID Department.

The major goals of the Lead ID department are to implement HTS campaigns that screen large compound libraries and to identify "lead" compounds that will drive drug discovery research programs forward to a clinical drug candidate. We intend to accomplish our goals by leveraging novel high-throughput screening technologies. When fully realized, the Lead ID department will provide the following research related activities:

Support of HTS research within TSRI at La Jolla, California and in Palm Beach County, Florida.
Management of Scripps extensive (> 600,000 member) drug screening compound collection for HTS, Medicinal Chemistry and Pharmacology efforts.
Assistance for biomedical researchers with their development of HTS compatible assays.
Exploration and implementation of novel technologies for the advancement of HTS.

Highlights of our 2005 activities are presented below.

HTS Laboratory Construction

The Lead ID department is in the process of building a state-of-the art HTS laboratory at Scripps Florida. In addition to a fully-staffed HTS assay development laboratory, the centerpieces of the laboratory are two automated robotic systems sold by Kalypsys, Inc.

The first robotic system is dedicated entirely to executing HTS campaigns. It has the ability to test over one million assay wells per day in 1536-well plates, and has an on-line storage capacity of over a million compounds. By design, the HTS System is capable of running 24 hours a day, 7 days a week and can perform both biochemical and cell-based HTS assays. Because the HTS system performs assays in 1536-well format microtiter plates (assay volumes of ~10 microliters / well), HTS campaigns can be completed rapidly & economically.

The second robot, the "Hit-Picker" system, stores a copy of the entire HTS compound collection on-line. It has the automation to instantly retrieve & reformat any member of the collection to a 384 or 1536 well plate. This robot will be used to support medicinal chemistry effort after an HTS campaign is completed, allowing scientists to rapidly select "hits" for further pharmacological analysis.

Currently, the final installation and testing of the Kalypsys robotic systems will be completed in November and will be ready for use by the start of 2006.

Compound Collection Acquisition & Management

In addition to setting up the HTS facility, Lead ID is concurrently acquiring a proprietary collection of over 600,000 drug-like compounds to be managed and maintained for HTS efforts. This collection will include important commercial sources such as Asinex (e.g its "rule of three" collection), Chembridge (e.g. its GPCR collection), ChemDiv, Key Organics, Maybridge, Peakdale, Biofocus, Deltagen, Life Chemicals and Enamine. Additionally, it will be supplemented with novel compounds from Scripps' internal medicinal chemistry efforts. To support drug target profiling and facilitate grant writing efforts, smaller collections will be established. Currently, our goal is to have the compound acquisition completed & ready for HTS efforts by the first quarter of 2006.

Research Collaborations

Scripps has been designated a member of the Molecular Screening Center Network (MLSCN), as part of the NIH Roadmap initiative (http://nihroadmap.nih.gov/). In collaboration with Hugh Rosen's laboratory, Lead ID will support the implementation & execution of HTS campaigns approved for Scripps' MLSCN goals. After completion of the HTS effort, the resulting data will be made publicly available through PubChem, to aid in the discovery of probes that explore the functions of major components of the cell in health and disease.

As part of our commitment to the State of Florida, Lead ID is also setting up processes for Florida academic researchers to access our HTS expertise. This will be facilitated by creation of a specialized compound collection and screening paradigm tailored to academic research efforts.

Finally, Lead ID is interested in forming research collaborations with the scientific community that investigate and develop HTS engineering & assay technologies, or implement HTS campaigns on targets of pharmaceutical research interest.