Rajarshi Guha, Ph.D., research informatics scientist at NIH Chemical Genomics Center (NCGC), was scheduled to speak at the meeting about his research. NCGC is a high-throughput screening center with expertise in HTS assay development and assay optimization.
Upon receipt of an assay and subsequent optimization, the center screens the Molecular Libraries Small Molecule Repository (MLSMR) of about 400,000 molecules, along with other libraries. “From the primary screening, we get our set of hits and, in some projects, have access to structural information for follow-up structure-activity relationship (SAR) studies,” he explained.
“Our use of structural biology at that point is to identify useful molecular series for secondary screening, and, in some cases, it’s also used to directly elucidate more specific SARs in the lead-optimization process.”
Dr. Guha has focused on linking small molecule ligand SARs with RNAi screening assays to probe novel drug targets. His group is also trying to develop a systems-based approach in which results from RNAi screens are integrated with results from small molecule screens using MLSMR. “We are trying to get more high-resolution information and, for that reason, we are moving to high-content screening on both small molecules and RNAi.”
There is a major challenge in performing such phenotypic matching, though—the mechanism for small molecule hits and RNAi molecule hits differ substantially from one other. “So when a molecule and an siRNA are both identified as active in their respective assays, that doesn’t mean that the small molecule is hitting the same target as that of the RNAi knockdown,” said Dr. Guha.
As a result, Dr. Guha and his team are spending a lot of time performing pilot testing and tweaking their methods of phenotypic matching. “I think there’s a wide scope in this approach, in that, even though high-content imaging screens are time-consuming, the end result is a rich set of data that allows us to go toward a holistic picture of what’s going on at the small molecule level.”