Future Plans for HTS Core Development
Large-scale Protein Expression
Having sufficient quantities of reagents is a basic prerequisite to successful high-throughput screening (HTS). Often, supplies of target proteins are limited because most academic labs do not have the capability to produce the necessary amount of proteins. We plan to consult with the experts in City of Hope’s Center for Biomedicine & Genetics to establish large-scale protein expression capability to improve the protein supply bottleneck.
Addition of High Content Screening (HCS) Capability
Carrying out highthroughput cell-based “phenotypic” screening (HCS) requires integrated instrumentation and informatics infrastructures. These include automated digital microscopy, image analysis and data mining software, as well as a data management package. These infrastructures allow researchers to measure multiple end points/parameters simultaneously for every sample. They can then use advanced algorithms to dissect and distill useful information from the complex data set. We believe HCS capability will advance drug discovery on multiple fronts, including target identification and validation, primary and secondary screening, compound profiling and lead optimization.
Development of In Silico ADME Prediction and In Vitro ADME Testing
One of the major obstacles in drug discovery and development is the high failure rate of compounds during clinical trials. Many of the compounds fail because of poor absorption, distribution, metabolization and excretion (ADME) properties. With the advancement of computational power and methodologies, it is now possible to performin silicocalculation of a number of important ADME properties including aqueous solubility, log P octane/water, Caco-2 cell permeability and human serum albumin binding. By combining thein silicocalculation within vitroADME testing to confirm the predicted values, we can more accurately target selection of lead compounds for further development. The Biomedical Informatics Core will purchase ADME prediction software and make it available through City of Hope’s intranet. The HTS Core will establishin vitroADME assays, including Biomimetic Artificial Membrane Permeation Assay (BAMPA), Transil Human Serum Albumin (HSA) Binding Assay and Cytochrome P450 Isoenzymes Assay, to obtain experimental data on key ADME properties for compounds of interest.