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In 2005, Scripps Florida created the Translation Research Institute (TRI), which has capabilities for several aspects of early-stage drug discovery, including Assay Development, including Cell Lines, HTS Campaigns, Compound Management, Cheminformatics and Instrumentation Development.

Overview of Lead Identification

Essential components of successful Lead Identification are summarized in the figure below.

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Lead Identification is a collaborative effort between biology, engineering, information technology, chemistry and pharmacology staff. The first step of Lead Identification is called “Assay Development” [Step 1]. Assay development starts with the nomination of a relevant “target” (for example, a kinase, G-protein coupled receptor, pathogenic bacterial strain) and the creation of an “assay” (experiment) that enables the testing of compounds for pharmacologic activity against that target. To maximize throughput and economy of a high-throughput screening (HTS) campaign, the assay is adapted to microtiter-plates and validated for HTS using specialized equipment. After completion of this step, the assay is considered “HTS-ready.” It is then mounted on our fully-automated screening platform, and the “HTS Campaign” begins [Step 2]. During the HTS campaign, each compound in our 600,000-member collection is screened against the target, with the ultimate goal of discovering compounds with pharmacologic activity against the target. All data emerging from HTS is uploaded to our corporate databases for further processing.

After data passes Quality Control (QC) metrics, cheminformatics tools are implemented to prioritize compounds of interest. For example, these tools can be used to determine an active compound’s selectivity to the target, cytotoxicity, structure-activity relationships (SAR) or even physical parameters such as solubility and logP values. Upon completion of analysis, compounds are gathered for further testing in Lead Optimization assays that confirm activity, profile selectivity, or determine mechanism of action [Step 3]. These compounds can come from Lead Identification’s library, be procured from vendors or even re-synthesized if not readily available.

A successful Lead Identification effort results in a set of well-characterized compounds, “Leads,” with promising SAR as well as desirable pharmacologic and physical properties. These compounds can then be further characterized and refined via downstream efforts, such as Medicinal Chemistry and DMPK, and in vivo studies. These activities can be executed in our collaborator's lab, or within other facilities located at Scripps.

Click on the following links (or use the side menu at the top of the page) to find out more details on our capabilities in each area:

Assay Development

Cell Lines

HTS Campaigns

Compound Management

Cheminformatics

Instrumentation Development

Assay Development

The overarching goal for Assay Development focuses on the timely delivery of robust and well validated assays to HTS Robotics. Our ability to clone, express and purify proteins, as well as to stably or transiently transfect cells from our own cell bank gives us the ability to design and develop new assays from scratch. We are not restricted to development of HTS assays for mammalian targets. Utilizing our dedicated microbiology facility we also focus on the discovery of novel antibacterials, antiparasitics and antifungals.

In most cases, assays are first developed either in the 96- or 384-well plate format and further miniaturized to 1536-well plate format for HTS. Our expertise encompasses both biochemical and cell-based assays development, covering a large panel of popular readouts such as absorbance, luminescence, fluorescence, fluorescence polarization, FRET, QFRET, TRF, TR-FRET (HTRF, LANCE, Delfia), FLIPR and AlphaScreen/AlphaLISA, but also custom assay formats such as phenotype readout assays. The breadth of our assay development capability is demonstrated by the range of target classes and assay platforms we already addressed, viewable below:

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Cell Lines

The SRIMSC has procured over 120 cell lines which are available for access and use by Scripps (TSRI) faculty. These are available to support GPCR interrogation via beta-lactamase detection involving numerous pathways. If interested please contact us.

(Click image to download the full list of available cell lines)

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HTS Campaigns

The Lead Identification Division at Scripps Florida has set-up a state-of-the art HTS operation to support Scripps’ intramural HTS efforts and has expertise in adapting biological and biochemical bench-top assays into high-throughput screens.

This centralized HTS facility supports early-stage drug discovery efforts of industrial and academic collaborators. The facility is anchored by two fully automated robotic screening platforms; one to support 1536-well based HTS efforts and the other to manage Scripps’ small-molecule compound collection. Additionally, the facility has the laboratory equipment and staff expertise to facilitate upstream HTS assay development and downstream hit validation efforts.

Lead ID has screened a large variety of targets using numerous different detection technologies and assay formats. A breakdown of public domain HTS campaign types by category can be found in the specific charts below:

(Click Chart to Enlarge)

To access a full table with individual breakdowns of the public domain campaigns run during that time frame, please click HERE.

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Compound Management

The Compound Management facility at Scripps Florida provides core functionality for the solubilization, cherry-picking, storage, reformatting, transfer and replication of compounds. These Compound Management processes are supported by laboratory automation which allows work to be performed in microtiter plate densities up to 1536-well format with transfer volumes as low as 500nL. Typically, these processes are utilized to support Medicinal Chemistry, HTS and Assay Development efforts for both in-house and external collaborator’s projects.

Lead Identification’s compound management automation allows samples to be solvated and transferred between various labware types, densities and formats. Common liquid handling processes include performing compound titrations, reformatting compounds from lower to higher density labware, microtiter plate replication, compound transfer and cherry-picking of compound libraries. All physical liquid handling procedures are matched with appropriate data management processes to ensure the fidelity of data associated with all samples and labware which pass through the Compound Management facilities.

All Compound Management processes utilize a barcode based inventory system to ensure compound integrity throughout the life of the sample. This system tracks sample genealogies, LC-MS QC reports and sample availability. In addition, the inventory system has been integrated with sample storage automation which provides seamless sample access to end-users and ensures samples are available on demand.

A proprietary setup based on Agilent’s Rapid Resolution HT technology allows for fast HPLC separations using small sample injections yet generating high resolution chromatograms. Sampling compounds directly from microtiter plates, ≤1uL of sample is needed for a 5-minute separation & analysis time. Data collected includes UV & TIC chromatograms, full UV peak spectrum analysis, APCI and ±ES mass spectral fragmentation analysis. Estimated compound purity as well as mass ion identification is automatically calculated using custom software, and key QC attributes (compound ID, structure, compound mass & purity) are exported & stored in our HTS database. A complete flowchart of this process can be viewed here.

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Cheminformatics

Chemical series emerging from a successful HTS campaign can be analyzed and optimized at the Lead Identification facility through the use of computer-aided strategies. These include: (a) analysis of screening data to eliminate false positives and off-target activity, (b) prediction of physical and biological properties of small molecules to flag non-druglike functionalities and chemical reactivity, (c) molecular similarity and diversity searching, (d) Structure Activity Relationship (SAR) analysis and SAR by purchase from commercial libraries (> 5 million compounds), (e) virtual library enumeration of active lead compounds, and (f) design and custom synthesis of lead-candidates and novel analogs.

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Instrumentation Development

The Plate Auditor (US Utility Patent US8644547) is a platform for the detection and classification of features found in different storage containers. It performs fully-automated, rapid (<1 min) measurements. Measurements are accomplished non-destructively and without contacting the sample or the sample container. The Plate Auditor platform can be customized to applications in life sciences, drug discovery and analytical chemistry.

Figure 1: The Plate Auditor

The Plate Auditor (Figure 1) has been designed specifically for compound management (CM) users in HTS labs. It has been customized to detect and classify artifacts found in compound storage containers, for example, HTS-compatible microplates. These artifacts include: (a) insufficient volume of compound, resulting from inaccurate/imprecise dispensing of compound by liquid handlers, (b) compound precipitation resulting from improper compound storage and/or dilution, and (c) colored compounds that interfere with HTS assay readout (see Figure 2).

Figure 2: Sample Artifacts detected & classified by the Plate Auditor. Representative artifacts as seen in a 384-well microtiter plate: A) empty well, B) colored compound, C) bubbles, D) partially-filled well, E) precipitate and F) a "normal" filled well.

The Plate Auditor platform consists of an HTS plate-reader and user-friendly software to initiate protocols and view results. The platform can be run in “stand-alone” mode. Optionally, it can be integrated with a robotic platform, or configured to automatically query & compare Plate Auditor analysis results to data stored in a LIMS or corporate database.

For more information on the Plate Auditor or custom instrumentation development, please contact us at This e-mail address is being protected from spambots. You need JavaScript enabled to view it

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