Early Stage Hit Triage for Plant Chemical Genetic Screens and Target Site Identification

The increasing use of plant biological screens of large compound libraries to discover informative chemical probes for plant chemical genetics requires efficient methods for hit selection and advancement. Downstream target identification and validation studies with selected chemistries can also be resource-intensive and have a significant failure rate. Several steps and considerations for early stage hit triage are outlined to increase the probability of success that downstream studies with the chemical probe will be robust and productive, especially for target site discovery. Conversely, problematic compounds can be shelved or avoided entirely, saving time and resources. These steps include assessment of compound availability, purity, stability and solubility; determination of the biological dose–response; early and iterative evaluation of analogs; avoidance of promiscuous “frequent-hitters”; consideration of physicochemical parameters affecting compound bioavailability and mobility, use of “low-barrier” biological testing systems; and assessing the potential for compound metabolism or bioconversion.