On this Halloween night, let’s talk about something that has bugged me for a while. I recently realized that I tend to make contradictory remarks in my discussions with faculty colleagues and students. Most of these polarizing statements come out unintentionally. For example, I often talk about my lab’s interest in chirality. In doing so, I naturally imply and state the importance of asymmetry in drug design. Interestingly, as I switch to discussing some elements of my lab’s joint work with the Structural Genomics Consortium (SGC), I am forced to remember about our recent findings that chiral fragments are underperforming in our search for protein binders. Just to remind you about what we do: we run soaking experiments that are aimed at identifying small molecule fragments that bind to proteins. We literally take cocktails of small molecules, soak protein crystals in them, and occasionally get co-crystals. Peter Brown’s group at SGC is doing some really nice work in this regard. As I already mentioned, we have had comparatively little luck with the so-called “3D fragments”, or molecules that are more complex by virtue of having chiral centers. So tell me why should I, in a scientific discourse, continue to overstate the importance of chiral compounds? I have a contradiction here, ladies and gentlemen.
Molecular complexity is important, but mainly in process research, at a stage when one needs to prepare large amounts of a known (potentially complex) target. The corresponding molecule has likely emerged from iterative rounds of optimization that have inevitably led to increased molecular weight and structural complexity. On the other hand, the track record of chiral molecules at the discovery stage is not too impressive. What I just mentioned extends beyond fragment screening. In fact, if we go back 12 years, we find an interesting report by Hann and colleagues that suggests that collections enriched in very complex molecules generally have a low chance of individual molecules binding to protein targets. The authors suggest that it is far better to start with less complex molecules and increase the potency by increasing the complexity. These findings are correlated with experimental observations we have recently made in fragment screening (and may publish at an opportune time). For me, the implication is clear: avoid chiral centers and complex structures early on. Those who think that complexity favors discovery are profoundly misled. Here is that thought-provoking Hann paper:
There is an interesting consortium in the UK, called 3Dfrag (http://www.3dfrag.org), whose stated objective is to exploit complex chiral structures in fragment screening. I would be very interested in seeing publications that are hopefully going to come out of their work in the future. For now, I am not convinced that there is definitive data suggesting that chiral molecules enable discovery. So, let’s turn it down a notch with overzealous statements about asymmetric catalysis. Prove me wrong, though, by all means.