This blog is meant to allow Fragment-based Drug Design Practitioners to get together and discuss NON-CONFIDENTIAL issues regarding fragments. But what do you do once pkc iota antibody get hits?
The researchers, who had previously identified a xanthine-containing series of inhibitors, pared this back to fragment-sized compound F1. The fact that 14 of the 17 molecules synthesized were at least an order of magnitude more potent than the initial fragment is satisfying, though it is worth noting that bromodomains are not the most difficult targets. Also, all of the new molecules have lower ligand efficiencies than the initial fragment. Ten years ago today Teddy launched Practical Fragments with a simple question about screening methodologies. There has since been a trend toward smaller fragments, driven in part by empirical findings that smaller fragments have better hit rates, in agreement with molecular complexity theory. At some point, though, ever smaller fragments will mean lower hit rates: fragments that are too small will bind so weakly they will be difficult to detect.
And practical issues arise: organic molecules with just a few non-hydrogen atoms are often volatile. Therefore, we’re revisiting this question: What is the smallest fragment you would put in your library? As long as we’re on the subject of libraries, how many fragments do you have in your primary screening library, or how many do you screen on a regular basis? Please vote on the right-hand side of the page. Please feel free to leave comments too. Hard to believe we’re already halfway through the year, but there are still some exciting events ahead, and 2019 is already starting to take shape. August 19-23: The 256th National Meeting of the American Chemical Society, which will be held in Boston, includes a session on “Best practices in fragment-based drug design” on August 20.
September 25-28: CHI’s Discovery on Target will also be held in Boston, and there will be lots of presentations of interest to readers of this blog, particularly in the Lead Generation Strategies track. October 7-10: Finally, FBLD 2018 returns to San Diego, where it was born a decade ago. This will mark the seventh in an illustrious series of conferences organized by scientists for scientists. March 24-26: The Royal Society of Chemistry’s Fragments 2019 will be held in the original Cambridge.
This is the seventh in an esteemed conference series that alternates years with the FBLD meetings. April 8-12: CHI’s Fourteenth Annual Fragment-Based Drug Discovery, the longest-running fragment event, will be held in San Diego. Add it to the comments or let us know! The first fragment-based drug to reach the market, vemurafenib, targets a mutant form of the kinase BRAF. Most kinase drugs bind to the so-called hinge region of the protein, where the adenine moiety of ATP binds. Unfortunately this molecule did not have good pharmacokinetic properties, so the researchers sought a new series.