Last year we launched a puzzle series in efforts to help combat the Crimean-Congo Hemorrhagic Fever (CCHF), a severe and often fatal zoonotic disease caused by a tick-borne virus. As previously mentioned in the blog post, our focus has been on targeting the viral-encoded Ovarian Tumour (OTU) protease, which plays a pivotal role in the replication process of CCHFV by subverting the host's immune responses.
In our initial puzzle series, we presented the players with a challenging task: designing compounds that could effectively bind to the large and superficial interaction surface of the CCHFV-OTU protease. Despite the collective efforts and innovative solutions put forth by the community, the first round of limited testing yielded no active compounds among the 10 selected for experimental validation.
However, we remain undeterred in our pursuit of identifying viable medical probes for CCHFV. In response to the outcomes of the initial screening, we are launching revisiting series of puzzles with the aim of generating a diverse pool of potential compounds for further testing. Leveraging the creativity and problem-solving skills of the Foldit community, we are confident that we can overcome the challenges posed by the complex binding pocket of the CCHFV-OTU protease.
Together, we have the opportunity to make a meaningful impact in the fight against CCHFV!
What can you tell us about the 10 CCHFV compounds that were selected for experimental validation? For example, what puzzles did they come from, what scores did they get in these puzzles, who designed them, and what are their structures? We get very little feedback (other than puzzle scores) about our designs, but somehow you chose just 10 for these experiments. How did you choose those 10?
If you can give similar details for the other series of Small Molecule Design puzzles, I think it would be very helpful. In CACHE Challenges #2 and #3, for example, you have already chosen around 300 molecules in all for synthesis and experiments. So far, we only know about perhaps 8 of them. What would it hurt at this point to share with us more information about the rest of the 300 compounds? Without giving their structures, you could at least tell us which puzzles they came from, what scores they got in these puzzles, and who designed them.
Agreed: it would be good to hear about the failures as well as the successes.
The 10 you chose for the CCHFV experiments, at the time you chose them, stood out from the rest. At that time, they looked like the best bets. What made them stand out? Were they all library compounds? What ligand subscores did they get? Were they high on bonding? Were they low on clashing? Even though they didn't end up winning the championship game, they made it into the top 10, which is better than most and certainly not a failure.
If you think of us players as lab rats doing operant conditioning experiments, and you want to increase certain behaviors (like playing Foldit better), it helps to have rewards now and then. It also helps to spread out those rewards to as many players as possible. Like if you only reward the same 3 rats every time, why do you expect the rest of the rats to keep playing? Don't you want to have a team with a deep bench and plenty of enthusiastic players? Many systems, like the lottery, have some rare really-big rewards, a few more medium-value rewards, and then many low-value rewards. The different reward levels encourage more people to play. In Foldit, rewards could be recognition, feedback, or other kinds of personal acknowledgment. Some kind of proof that our efforts are important to you.
I am curious to know what player ligand where selected yes
