2267: SARS-CoV-2 Nsp3 CACHE Challenge 3: Round 2

Closed since about 3 years ago

Summary

• Created: February 17, 2023
• Expires: February 24, 2023 at 23:00 UTC
• Max points: 100

Description

Compete in a challenge to design a drug targeting the SARS-CoV-2 Nsp3 macrodomain. Use the small molecule design tools and the compound library panel to find library compounds which bind to the active site of the enzyme. -- Only compounds which come from the Compound Library panel and get the Compound Library objective bonus will be experimentally tested.

Note: To get the most out of the small molecule design tools, we recommend changing you view settings to the Small Molecule Design Preset.

For Round 1 we started you out with the enzymes natural substrate. For Round 2 we're picking a known decent binder (from a previous screening campaign) - one which doesn't have a phosphate group. Can you find derivatives (or new compounds) i the compound library which bind well to the protein?

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. 12,493
• 2. Contenders 70 pts. 11,762
• 3. Anthropic Dreams 47 pts. 11,500
• 4. chgf.vu.lt 30 pts. 11,070
• 5. Australia 19 pts. 11,040
• 6. FamilyBarmettler 11 pts. 10,930
• 7. Gargleblasters 7 pts. 10,845
• 8. Marvin's bunch 4 pts. 10,566
• 9. AlphaFold 2 pts. 10,534
• 10. L'Alliance Francophone 1 pt. 9,693

Top soloists

• 1. Bruno Kestemont 100 pts. 12,390
• 2. nspc 95 pts. 12,367
• 3. spvincent 90 pts. 11,734
• 4. Bletchley Park 85 pts. 11,580
• 5. Sandrix72 80 pts. 11,569
• 6. MicElephant 75 pts. 11,561
• 7. sitlux 71 pts. 11,552
• 8. grogar7 67 pts. 11,482
• 9. NinjaGreg 63 pts. 11,423
• 10. LociOiling 59 pts. 11,339

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. See this forum post for more discussion.)

Acid groups (max +1000)
Certain groups like carboxylate and phosphate would make compounds not ideal for drug usage. This gives a bonus if the compound is missing these problematic groups. (Show highlights regions of the molecule at issue.)

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.)

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.)

[Sandrix72]

My evolved solution do not appears here.
The client program was closed and restarted. Nothing happens. :(

[LociOiling]

I see Sandrix72 on the evo board, so I guess the ferrets work up and got busy.

[guineapig]

Why is the starting point of the frozen part in round 2 from the SARS-CoV-2 Nsp3 CACHE Challenge puzzle different from round 1? There are a lot of sidechains which are in another position. Therefore the segment values are worse (color turns into red). How can you compare the solutions from different rounds within the foldit community? This a competition against non-foldit teams. Which ones of the starting positions are the correct ones? Happened a change in the challenge?

[jeff101]

Please see https://fold.it/forum/discussion/intentionally-changed-starting-positions-of-the-sidechains-on-puzzle-2267-vs-2264-cache-challenge for some answers to guineapig's questions above.

[rmoretti]

The starting structures in both cases are experimental crystal structures of the Nsp3 macrodomain in complex with a ligand. It's a different ligand in each case. In Round 1 it was a co-crystal structure with the native substrate, and in Round 2 it's a co-crystal structure with an inhibitor compound identified from a screening campaign.

Different ligands do occasionally result in different sidechain (and backbone) positions for the binding protein. That's one of the purposes of changing up the protein structure – different protein contexts present a different environment to the binding pocket, which mean that different ligands may be slightly better or worse at binding. By running puzzles with multiple different protein contexts, we (potentially) get a wider diversity of compounds that score well, which gives us a better chance of finding one which will actually work experimentally.

You're correct in that the different contexts make it slightly more difficult to do the post-puzzle compound assessment, but in generally we don't really compare the Foldit scores themselves between puzzles (for the small molecule design puzzles). We use the Foldit scores to rank designs within a single puzzle, but we're using various redocking approaches to validate and rank the compounds between the puzzles. When we do the redocking we can put in some sidechain and backbone flexibility, as well as do the redocking against multiple protein contexts and look at the consensus.

[Sandrix72]

The server do not refreshes the compound library even in several hours. :(
How can i try new solutions this way?

[BootsMcGraw]

It's now been over twelve hours, and I still can't get a response from the Compound Library. Please extend the deadline of this puzzle, as it is unfair to expect us to play with broken tools.

[rmoretti]

Sorry about the issue with the compound library. The ZINC server we use for the search (from docking.org) looks to be down currently. Hopefully that should just be temporary, and it will be back soon and can work on the backlog of submitted structures.