Today is our last paper on high throughput screening (HTS) techniques. We’re back to discovering drugs on this one but the premise is quite different for this particular screen. Whereas other papers we’ve done so far have involved finding novel drugs for known targets or identifying drugs that produce novel behavioral phenotypes, this paper is about finding novel drugs for enzyme targets that are not fully characterized. The paper is: “Identification of selective inhibitors of uncharacterized enzymes by high-throughput screening with fluorescent activity-based probes”, Bachovchin et al., 2009, Nature Biotechnology [PMC].
The genome era has brought in a new age in terms of understanding and identifying the number of genes in mammalian and other genomes. While we have a good idea of where genes lie in genomes and what their structure looks like from all of this sequencing, we do not necessarily understand what these genes do based purely on their sequence. While we can make some good guesses (probably better than a guess) on whether such genes are enzymes, GPCRs or other types of proteins based purely on homology, we cannot necessarily understand their function within cells or whole organisms based purely on sequence data. For almost every protein, we understand how it works within complex systems because we have tools to probe its function. Sometimes these tools involve genetic manipulations or knockdown technologies but more often these tools to probe function depend on pharmacological manipulation of protein function. Therein lies the problem. If you know of an uncharacterized enzyme or receptor and have some idea of its substrates or its receptor class, but not much else, how do you screen for inhibitors or activators of that enzyme or receptor. In the case of enzymes we can generally identify at least one of their substrates based on sequence homology but that doesn’t help you to put together a functional screen in all cases. A way around that is to perform activity based protein profiling (ABPP): Continue reading