Most of the talks were pre-recorded, which meant that speakers could answer questions in real-time in a chat box. More importantly, the talks are available to attendees for a year, which means you can watch relevant talks from other tracks, thus relieving the FOMO inevitably experienced in meetings of this sort. It also means you can replay particularly relevant talks to your colleagues, though I wonder if this also makes speakers wary about disclosing the freshest information. The on-demand access to posters is especially useful, as it is too easy to overlook these in the usual melee. The organizers also did a nice job of trying to foster the feel of an in-person meeting, with multiple live Q&A panels, breakout sessions, and other interactive events.
There are drawbacks, chief among them the lack of spontaneous and serendipitous meetings that are one of the main benefits of in-person conferences. And of course there were technical snafus. Most talk slots were only 20 minutes, but some of the pre-recorded talks went as long as 28 minutes, forcing attendees to choose between missing part of one talk or another (or a live Q&A). Although you can fast-forward, it would be nice if you could also speed up playback speeds. And on at least one occasion the wrong talk was played, though I was able to go back and watch the correct one later.
But enough about process, what about the event itself? With dozens of talks over four days I can’t be exhaustive, so please add your thoughts to the comments.
Key to the success of these types of approaches is what plenary speaker Phil Baran (Scripps) calls “boring chemistry” that consistently works in multiple contexts. To Phil, inventing chemistry that becomes boring is a great compliment, and he showed examples of running interesting transformations in tea, beer, and wine. As the name of this blog suggests, I have a soft spot for this sort of thing, and wholeheartedly agree with his statement that “you can’t give a Nature paper to a cancer patient.”
Alexander Statsyuk (University of Houston), Maurizio Pellecchia (UC Riverside), and Nir London (Weizmann Institute) all also discussed covalent lead discovery. Maurizio has been targeting lysine residues using sulfonyl fluorides and fluorosulfates; for the latter warhead he has been able to show reasonable pharmacokinetics in rodents. We’ve previously discussed some of Nir’s work, but here he described a nice case study against the challenging anti-cancer target Pin1 which led to potent and surprisingly selective chloroacetamides with activity in mice.
Interestingly, while chloroacetamides were the main class of MPro fragment hits, the three most advanced lead series Frank mentioned are all non-covalent. There were plenty of other nice non-covalent fragment-based success stories too, including potent selective inhibitors of the lipid kinase Vps34 (Jenny Viklund, Sprint Biosciences) and selective inhibitors of one kringle domain of apolipoprotein(a) (Jenny Sandmark, AstraZeneca).
Amit Gupta described NanoTemper’s new Dianthus instrument, which relies on the temperature-related intensity change (TRIC) of a fluorophore bound to a protein. This is similar to their MST approach though it appears to be higher-throughput, and a paper benchmarking these techniques against DSF and SPR should be coming out later this year.
Also on the subject of thermal shifts, Justin Hall (Pfizer) gave a provocative presentation on using these to determine ligand affinities. He noticed a correlation in his own research, but the prevailing wisdom held that irreversible thermal denaturation (as seen for most proteins) would not provide thermodynamic parameters. Nonetheless, perhaps because proteins are fundamentally similar (consisting as they do of chains of 20-odd amino acid residues), the temperature-dependent Arrhenius functions and activation energies of unfolding are also similar, and thus for heating rates of 4°C/minute and 100 µM ligand one can extract dissociation constants. However, he did mention that this approach is restricted to reasonably tight ligands (KD < 20 µM). Also, if a ligand binds to the unfolded state of the protein, or to multiple sites, all bets are off.
In the interest of time I’ll stop here, but if you’d like to experience a virtual conference yourself, there will be a number of good FBLD talks at Discovery on Target next month, and I hope to “see” you there. But I especially hope that in-person conferences will resume next year once our industry – and competent governments – get COVID-19 under control.