Compete in a challenge to design a drug targeting the SARS-CoV-2 helicase. Use the small molecule design tools and the compound library panel to find library compounds similar to the starting compound which bind to the active site of the enzyme.
Note: To get the most out of the small molecule design tools, we recommend changing you view settings to the Small Molecule Design Preset.
This puzzle is part of Foldit's participation in the CACHE Challenge. From the set of all compounds submitted in the multiple rounds of puzzles, Foldit scientists will select up to 50 compounds based on the CACHE-provided criteria. Only compounds which are in a commercially available library will be selected, so it's beneficial to make use of the Compound Library panel to search for library compounds similar to your current design. But don't limit yourself to the compound library. You're more likely to get good results by alternating: optimizing the molecule with the small molecule design tools, find the closest library compound, then further refine it with the design tools.
For this puzzle series, we're looking to examine the Structure Activity Relationship (SAR) of the hit compounds from the previous series. As such, we ask that you attempt to find things which are similar to the starting molecule, rather than creating something completely new. There's a Similarity objective which should show when you're going too far afield.
Participation in CACHE puzzles is subject to the CACHE Terms of Participation, in particular “the Challenge IP [including Challenge Compounds] will be made freely available in the public domain pursuant to Creative Commons Attribution Only (CC-BY 4.0 or subsequent versions) licensing terms, with the intent that such Challenge IP may be Used and practiced by Users for any purpose”.
If only molecules in the compound library are going to be selected why not increase the compound library bonus to say 10,000? Right now it seems the compound library tool pays little or no attention to the ligand hydrogen bonds which both score well and provide specific binding. My best compound has 5 hbonds which score just over 2,000. But that bonus all goes when the compound library tool goes to work on it: it seems a lot fonder of adding random halogen atoms here and there than in maintaining groups that can form hbonds.
The starting compound looks just like a nucleotide, so it's easy to modify it like designing a DNA/RNA analog, by adding hbonding atoms to the base-analogue ring. Unfortunately it's not what an existing compound looks like, another fragment of this compound doesn't come with too much alternative especially with the cyanide as hydrogen acceptor.
Maybe next time better focus on the central ribose-like linker or the ring with cyanide for a better chance of library hits…
I'm not sure if increasing the library bonus too much is a good idea, it'd put a huge bias onto the starting compound that make it difficult to score higher than that. May lead to premature convergence that everyone is getting the same design without exploring further. Hard to find the right point, though, to keep the similarity while looking for diversity.
Meanwhile, the "error" searches may have been automatically rerun sometime in the last 24 hours or so. I'm not seeing any "error" entries in my list now.
