When a disease target is identified from our discovery biology programs, or from a collaborating laboratory, assays are developed and validated for high-throughput screening (HTS). The robotic screening center at IDRI consists of two parts. One is a purely biochemical screening operation and the other can screen compounds against virulent M. tuberculosis in a BSL-3 lab. IDRI’s BSL-3 facility allows screening of virulent Mtb with an expertise that only exists in a handful of locations worldwide.
The following approaches are available to IDRI, and all are being deployed:
· Physiology-based screening, which relies on physiological readout to screen and profile compounds, usually on cell-based assays, and is independent of target identity.
· Target-based biochemical screening, which is a paradigm based on knowledge of the function of a potential therapeutic target protein and its role in the disease. It involves biochemical assays on the protein in a cell-free system.
· Target-based whole cell screening, which is a hybrid of the two. Bacterial strains are constructed that over- and/or under-express a target protein. If a given compound is affecting cell growth via that target, it will exhibit different MIC values against the different strains. This should greatly improve the quality of the hits coming from screens by narrowing them down to those that specifically inhibit through the mechanism being studied
Under the Lilly TB Drug Discovery Initiative, IDRI researchers will use these techniques to discover new prototype molecules from a library of compounds provided by Eli Lilly & Company. Other compound libraries will be accessed as well. Efforts will be complemented with medicinal chemistry expertise to improve those molecules, generating more potent and deliverable analogs.
IDRI’s screening centers are automated with instrumentation and data systems that expand lead discovery efforts. IDRI’s robotics are designed for running cell-based screens as well as biochemical screens of purified protein targets.
