Targeted programs represent a good majority of drug discovery efforts. They allow for a convenient rationalization of the biological events leading to pathologies and the modulation of such pathological events. They are based on the hypothesis that the modulation of the target is of therapeutic benefit. As a consequence, the key tool for the identification of modulators is a biochemical assay where the activity of the target is measured.
At IRBM, we have developed, optimized and run several types of biochemical assays to support drug discovery efforts. They can be divided in two major areas:
- Enzymatic assays
- Binding assays
In both cases, the integrated environment that IRBM offers has the potential to generate better and more relevant readouts to the desired compound mode of action. We can produce and validate customized proteins and reagents, such as small molecules and peptide probes.
We highly value developing and running enzymatic assays, constantly monitoring:
- Enzyme purity and identity to avoid picking up unspecific activities
- Enzyme kinetics to ensure robust evaluation and comparison of compound activities (e.g. Km determination)
- Continuous quality control of the assay outcome
- Robust data analysis with no manual intervention and full traceability of raw data
In addition to purity, identity, quality control and data integrity, for binding assays we particularly focus on:
- The validation of the relevance of the in vitro binding event(s) for the subsequent functional effect
- The optimization of the binding condition for an improved evaluation and comparison of binding disruptors
Biochemical assays in drug discovery are very often accompanied by higher throughputs. With our extensive experience in high-throughput screening and early drug discovery efforts, we have a strong understanding of the key determinants to align biochemical assays and throughput. They are:
- Assay miniaturization to high density formats (up to 1536 wells/plate)
- Assay metrics (Z’, robust Z’, dynamic range, signal to background) optimization to achieve robust assays
- Microplate related issues and solutions.
Finally, we employ state of the art biochemical assays for in vitro ADME that are required for compound profiling and selection toward pre-clinical candidates. We include CYP inhibition assays, hERG binding assay and other standard ADME assays.