2222: SARS-CoV-2 helicase CACHE Challenge: Round 7

Closed since over 3 years ago

Summary

• Created: November 04, 2022
• Expires: November 11, 2022 at 23:00 UTC
• Max points: 100

Description

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 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 100 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.

This round adds a Compound Library bonus. You get a massive 2000 point bonus for having an compound which is in the compound library. (You may need to submit the compound to the Compound Library Panel first.) Additionally, you can now load saved structures from previous rounds (Round 1, 2, 3 & 6 -- Round 4 & 5 are not included due to the different starting structure.)

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”.

Top groups

• 1. Go Science 100 pts. 20,389
• 2. Contenders 70 pts. 20,381
• 3. Anthropic Dreams 47 pts. 20,321
• 4. Gargleblasters 30 pts. 20,188
• 5. FamilyBarmettler 19 pts. 19,404
• 6. Marvin's bunch 11 pts. 19,313
• 7. Australia 7 pts. 19,141
• 8. AlphaFold 4 pts. 19,016
• 9. Hold My Beer 2 pts. 18,056
• 10. L'Alliance Francophone 1 pt. 17,782

Top soloists

• 1. Bruno Kestemont 100 pts. 20,384
• 2. guineapig 94 pts. 20,381
• 3. MicElephant 87 pts. 20,347
• 4. gmn 81 pts. 20,308
• 5. dcrwheeler 76 pts. 20,305
• 6. ucad 70 pts. 20,292
• 7. maithra 65 pts. 20,253
• 8. Sandrix72 60 pts. 20,215
• 9. HuubR 56 pts. 20,188
• 10. Aubade01 52 pts. 20,059

Comments

[rmoretti]

Objectives

Objectives in this puzzle are driven primarily by the evaluation criteria used by CACHE.

Maximum bonus: +11 000

Compound Library (max +2000)
Gives a bonus if your current compound is in the library. This uses a local cached version of the Compound Library search results to determine if the compound is in the library. If you manually create a compound that happens to be in the library (or if you load a shared solution with an on-library compound), you may need to submit the compound to the compound library search and wait to get the results back before the objective can properly recognize that the compound is in the library. (If the objective is not updating, try wiggling the structure.)

2/3/4 ligand Hbonds (max +1000 between the three)
To inhibit the helicase, having hydrogen bonds to particular atoms that would otherwise be involved with RNA binding is helpful. These three objectives give bonuses for having ligand/protein hydrogen bonds to specific atoms. You'll get +500 for 2 hbonds, +800 for 3 hbonds and +1000 for 4 or more hbonds. Show highlights the protein atoms which will contribute to your bonus. Note that you can form hydrogen bonds to any 4 of the highlighted atoms to get the full bonus. (Due to technical limitations, four protein-protein hydrogen bonds are also counted in the drop-down total.)

Torsion Quality (max +1000)
Keeps bond rotations in a good range. Using Wiggle or Tweak Ligand can fix bad torsions. (Show highlights torsions to be rotated.)

Number of Rotatable Bonds (max +1000)
Intended to keep the ligand from getting too big and floppy. You can reduce rotatable bonds by deleting groups or forming rings. (Show highlights rotatable bonds.)

Ligand TPSA (max +1000)
Topological Polar Surface Area - Keeps the polar surface area (including buried polar surface) low. To improve, try removing oxygens and nitrogens. (Show highlights atoms contributing to higher TPSA.)

Ligand cLogP (max +1000)
A measure of polarity - Keeps the molecule from getting too hydrophobic. To improve, try adding polar oxygens and nitrogens. (Show highlights atoms contributing to higher cLogP.)

Fraction of four-bonded carbons (max +1000)
Measures how carbons with bonds to four atoms ("sp3 hybridized") there are. Too few (too many double and triple bonded carbons) is bad. (Show highlights carbon atoms at issue.)

Bad Groups (max +1000)
Gives a bonus for avoiding groups that interfere with assays, or which are far from the compounds in the library. (Show highlights groups at issue.)

Molecular Weight (max +1000)
Keeps the ligand a reasonable size.

Synthetic Accessibility (max +1000)
Keeps the ligand from going too far from the compounds in the library. (Show highlights parts of the molecule at issue.)

[BootsMcGraw]

I don't understand this "compound library bonus". We get points if our structure matches something in the library? What's the point of design, then?

I started with a library compound, made the tiniest change to it, and immediately lost 2000 points. Why bother with a bonus you can't use?

Sorry… you guys just keep further and further alienating players with illogic like this.

[rmoretti]

@BootsMcGraw The issue we run into is that making small molecules is hard. Much, much harder than making new proteins. You can go online and order the genes for 100s of arbitrary new proteins in an afternoon, and get them shipped to you in a week or two for less than a couple hundred dollars per design. In contrast, making an arbitrary small molecule often takes months of effort and several thousand dollars of cost each – assuming you can make it at all. And an annoying thing about small molecule synthesis is that even a small change - adding or removing a single atom - can change the compound from something that's easy to make to something that is infeasable.

Ultra large compound libraries are a way around this. Instead of asking them to make arbitrary molecules, some chemical synthesis companies have gone through and listed all the chemical reactions they know how to do robustly, and then looked through their shelves of compounds to see what reagents they can feed into those reactions. This way they can predict what the results of those reactions would be and create a virtual library of billions of possible molecules which they think they can make cheaply and easily. Most of these compounds have never been made before (they're "make on demand"), let alone have been tested.

We were a bit lucky with the earlier small molecule design puzzles (e.g. VHL), in that Boehringer Ingelheim was sponsoring them and had put aside a not-insignificant amount of money and scientist resources to help evaluate and synthesize the molecules. But even then there was substantial reworking by the BI scientists to take the direct player designs and change them into something which was more easily synthesizable. With the CACHE challenge, we don't have that. CACHE is supporting compound procurement, but has very limited funds. If we want to submit the largest number of designs we can, then we need to make use of the ultra large libraries, and only submit compounds which are part of that list.

That's what the Compound Library Objective is attempting to reflect: the very real physical limitation that (realistically) the only compounds which are going to be submitted to CACHE for testing will be ones which can be ordered from Enamine ultra large library set. (The compounds which are being returned from the Compound Library.)

Off library compounds are useful, but only as a stepping stone to on-library compounds. So that's the recommended workflow. Take a compound, make it better with the Small Molecule Design tools, then submit it to the Compound Library to find which on-library compounds are close. Put those on-library compounds into the structure, use pull/shake/wiggle/scripts/etc. to optimize the binding of the on-library compound. Then repeat by trying to find modifications which might lead to different & better Compound Library search results. Yes, doing the modification will cause the Compound Library Objective to go down, but like other processes in Foldit (e.g. changing the clash importance), the hope is that this would be temporary. The hope is that once you re-submit to the Compound library you'll find a compound which causes the score to go even higher (just like you hope that the score goes even higher when you return the clash importance to full).