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2363: CACHE SARS Nsp3 Reranking challenge: Round 2

Closed since over 2 years ago

Intermediate Overall Small Molecule Design

Summary

Created
October 06, 2023
Expires
Max points
100
Description

This puzzle is a followup to the SARS-CoV-2 Nsp3 macrodomain design challenges. Help us rank potential active compounds!

Phase 2 of the CACHE challenge #3 is a ranking of all 1739 molecules which the various participants submitted for testing. In this puzzle you don't have free design with the Small Molecule Design tool, but you instead have the Ligand Queue which will provide you with a small number of possible compounds. You can then use the compound library panel to find related compounds specifically from the library of tested compounds. Then attempt to find the best binding position for the compounds.

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 this round, the ligand queue has a different set of possible compounds (these may get reordered to promote balanced sampling). In addition, we've turned on the Compound Library objective, which should make sure that compounds we're interested in make it to the top of the ranking. - Remember that you may need to submit Ligand Queue compounds to the Compound Library, wait for the results, and then hit wiggle on the compound before the Compound Library objective recognizes the compound. Bounce back and forth between the ligand queue and the compound library search to seek out compounds you think bind best.

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. Avatar for Anthropic Dreams
    1. Anthropic Dreams
    100 pts. 19,988
  2. Avatar for Go Science 2. Go Science 73 pts. 19,868
  3. Avatar for Contenders 3. Contenders 52 pts. 18,784
  4. Avatar for Gargleblasters 4. Gargleblasters 36 pts. 18,723
  5. Avatar for L'Alliance Francophone 5. L'Alliance Francophone 24 pts. 18,679
  6. Avatar for AlphaFold 6. AlphaFold 16 pts. 18,572
  7. Avatar for FamilyBarmettler 7. FamilyBarmettler 10 pts. 18,349
  8. Avatar for Marvin's bunch 8. Marvin's bunch 6 pts. 18,288
  9. Avatar for Australia 9. Australia 4 pts. 18,050
  10. Avatar for Team Schleswig-Holstein 10. Team Schleswig-Holstein 2 pts. 14,795
  1. Avatar for LociOiling
    1. LociOiling Lv 1
    100 pts. 19,983
  2. Avatar for Sandrix72 2. Sandrix72 Lv 1 93 pts. 19,839
  3. Avatar for Bruno Kestemont 3. Bruno Kestemont Lv 1 87 pts. 19,771
  4. Avatar for Galaxie 4. Galaxie Lv 1 80 pts. 19,757
  5. Avatar for Punzi Baker 3 5. Punzi Baker 3 Lv 1 74 pts. 19,443
  6. Avatar for dcrwheeler 6. dcrwheeler Lv 1 69 pts. 19,259
  7. Avatar for ucad 7. ucad Lv 1 64 pts. 19,145
  8. Avatar for jeff101 8. jeff101 Lv 1 59 pts. 19,061
  9. Avatar for rosie4loop 9. rosie4loop Lv 1 54 pts. 18,871
  10. Avatar for Bletchley Park 10. Bletchley Park Lv 1 50 pts. 18,784

Comments

LociOiling Lv 1

There is at least one compound in the ligand queue that causes a crash. So far just noted in #bugs-and-feedback on Discord.

I've been able to get the molecular weights, etc., for 28 of the 30 compounds. (I'm not counting the initial compound.)

The comments don't include this information, but the compound library bonus is 4000 points this round.

It sounds like all the starting compounds should be found in the compound library. (Except for the initial compound, with weight 411.414.)

To get the bonus, open the compound library panel and submit the current compound. The results should come back quickly.

Then click "Load Library". The library contents should appear in a few moments. The first result should be "exact match".

If you see "exact match", all you need to do shake for a second, followed by a brief wiggle. You should now have the compound library bonus.

Another option if you have the compound saved is to reload it from Open/Share Solutions when you see the "exact match". This should also get the bonus.

You do not need to click "Accept Compound" to get the bonus.

In general, if you have the compound library open when you load a solution, you should get the bonus immediately if it's in the results for a compound you submitted.

If you have the compound library open, you can start the ligand queue, and then submit library searches as you go. The compound library must be opened before the ligand queue. Unfortunately, you can't save a solution, shake, or wiggle while the ligand queue is open.

You can get the molecular weight and other properties in the "Small Molecule Properties" window, which opens with the "v" hotkey when the ligand is selected. You'll need to close or more the "Small Molecule View Options" window to see "Small Molecule Properties".

rosie4loop Lv 1

I'm getting compounds from ligand queue without library bonus. Current example has 2 library entries having similarity of 1.0 with the molecule from ligand queue. Maybe a mismatch in conformer generation -> regenerating smiles -> similarity calculation?

(edit: add screenshot)

LociOiling Lv 1

Update: as @jeff101 noted in #veteran today, we now have two additional compounds, giving a total of 30 plus the "initial" compound. The crashing problem has been resolved, but you should probably restart Foldit or at least reload the puzzle to make sure you have the current puzzle setup.

Here are the properties for the 30 compounds in the ligand queue. The "initial" compound with weight 411.414 it omitted, based on the comments for puzzle 2360. I also left out the aromatic and aliphatic ring counts on account of space.

# weight cLogP PSA heavy atoms H-bond donors H-bond acceptors rotatable bonds
1 204.042 2.62990 12.03 10 1 1 1
2 218.300 1.52980 36.36 16 1 3 1
3 231.215 0.23572 78.22 17 0 7 2
4 246.314 1.29920 58.95 18 2 5 5
5 262.357 2.59240 51.45 19 1 5 7
6 264.329 1.00380 76.02 19 1 6 5
7 271.263 2.19384 59.16 19 1 4 4
8 281.337 0.24970 78.71 19 2 6 3
9 290.319 2.14098 64.33 20 1 4 3
10 291.250 2.76390 60.17 19 0 4 3
11 297.366 1.65440 86.38 22 2 7 7
12 298.318 0.66080 98.58 21 3 7 6
13 299.274 0.59650 92.18 19 2 6 7
14 306.395 0.65840 86.80 21 2 7 6
15 313.327 3.46480 79.62 22 4 5 4
16 328.368 1.76750 71.89 24 1 6 7
17 343.261 1.16010 105.17 24 2 7 7
18 343.361 -0.36368 127.45 23 2 9 10
19 368.449 3.38088 61.17 25 0 4 4
20 376.428 1.51610 115.40 28 2 10 2
21 380.426 -0.26300 93.85 26 0 9 3
22 385.445 3.36860 79.81 27 0 7 7
23 385.552 3.88500 54.34 28 1 5 8
24 388.424 2.57140 96.26 27 2 7 8
25 390.417 1.32140 118.32 27 2 8 8
26 396.245 3.06470 66.39 23 0 3 3
27 410.358 2.69010 40.62 28 0 4 6
28 421.457 1.55060 126.81 31 2 9 5
29 433.512 2.96514 97.22 32 3 8 7
30 451.918 3.56834 102.31 32 0 9 8

LociOiling Lv 1

Here are the SMILES strings for each compound, now updated for all 30 compounds. The SMILES came from hand transcriptions of the string shown for each of the ligand queue entries. Errors are possible, but generally transcription errors mean an invalid SMILES string. All of these strings at least loaded into Jmol and produced the chemical formulas shown here.

# weight SMILES formula
1 204.042 CNc1c(F)cccc1Br C7H7BrFN
2 218.300 CC1C(O)CN1c1ccnc2c1CCCC2 C13H18N2O
3 231.215 Cc1cc(Cn2nc3cnccn3c2=O)on1 C10H11N5O2
4 246.314 C#CCNC(=O)NC1CCCCC1n1cccn1 C13H18N4O
5 262.357 CCC(CC)C(CNc1cccc2nncn12)OC C14H22N4O
6 264.329 CC(C)Cn1cc(NC(=O)C2CCNC(=O)C2)cn1 C13H20N4O2
7 271.263 Cc1cc(C(=O)OCC2CC(F)(F)C2)c(=O)[nH]c1C C13H15F2NO3
8 281.337 OC[C@@H]1CN(c2nc3cccnc3s2)C[C@@H](CO)O1 C12H15N3O3S
9 290.319 N#CCC1(O)CN(C(=O)c2cc3cc(F)ccc3s2)C1 C14H11FN2O2S
10 291.250 CS(=O)(=O)c1cccc(-c2nc(C(F)(F)F)co2)c1 C11H8F3NO3S
11 297.366 CN(CCCc1cc(-c2ccccc2)n[nH]1)Cc1nn[nH]n1 C15H19N7
12 298.318 CC(O)CNc1cc(N2C[C@@H](F)C[C@H]2CC(=O)O)ncn1 C13H19FN4O3
13 299.274 O=S(=O)(CCC(F)(F)F)NCCc1cc(O)ncn1 C9H12F3N3O3S
14 306.395 CN(CC(=O)NCC1(C)CSC1)c1ncnc2nc[nH]c12 C13H18N6OS
15 313.327 Nc1nc(NCC2(C(F)(F)F)CCCCC2)c2cc[nH]c2n1 C14H18F3N5
16 328.368 O=C(COCCOc1ccccc1)N1CCc2ccnc(O)c2C1 C18H20N2O4
17 343.261 O=C(OCCc1cnc(=O)[nH]c1)c1cc(C(O)C(F)(F)F)ccn1 C14H12F3N3O4
18 343.361 COC(=O)CCNC(=O)CSc1nc(=O)[nH]c(C)c1C(=O)OC C13H17N3O6S
19 368.449 N#C[C@@H]1CN(S(=O)CC2CCCCC2(F)F)C[C@H]1c1ccccc1 C18H22F2N2OS
20 376.428 c1nc(N2CCC3(CC2)CCN(c2ncnc4[nH]ncc24)C3)c2cn[nH]c2n1 C18H20N10
21 380.426 COc1ccc2c(c1)N(C)CCN2S(=O)(=O)c1cn(C)c(=O)n(C)c1=O C16H20N4O5S
22 385.445 CCN(C(C)=O)c1nc(C=CC(=O)c2cccc(N3CCOC3=O)c2)cs1 C19H19N3O4S
23 385.552 CCCCC1CCC(C(=O)N2CCC(NC(=O)c3ccn(C)c3)C23CC3)CC1 C23H35N3O2
24 388.424 COc1ccc(OCc2nnc(SCC(N)=O)n2-c2ccccc2F)cc1 C18H17FN4O3S
25 390.417 O=C(C=Cc1ccc[nH]1)O[C@H]1CS(=O)(=O)C[C@@H]1OC(=O)C=Cc1ccc[nH]1 C18H18N2O6S
26 396.245 O=C(c1nc(Br)c2c(F)cccn12)N1CCCC1c1nncs1 C14H11BrFN5OS
27 410.358 O=C(N1C[C@H]2[C@@H](C1)[C@@H]2C(F)(F)F)C1(C(=O)N2C[C@H]3[C@@H](C2)[C@@H]3C(F)(F)F)CCC1 C18H20F6N2O2
28 421.457 CCn1c(=O)[nH]c(=O)c2c(C(=O)NC3CCc4cnccc4C3=O)cc(C(C)C)nc21 C22H23N5O4
29 433.512 Cc1cc2ncn(CC(O)CNCc3c[nH]nc3-c3ccc4c(c3)OCCO4)c2cc1C C24H27N5O3
30 451.918 Cc1nc2ncnn2c(C)c1CCC(=O)N(Cc1nnc(-c2ccc(Cl)cc2)o1)C1CC1 C22H22ClN7O2

Sorry about the formatting, I haven't found a way to control table properties in Foldit's implementation of Markdown.

I did find a way to escape the @ signs in SMILES string to avoid creating spurious links. Add a backtick around the SMILES string did the trick. There must be a space between the backtick and the vertical bar used to delimit the table columns.

rmoretti Staff Lv 1

The issue with the ligand in the ligand queue which is causing a crash should be fixed. You may need to restart your client to pull in the updated puzzle files.

rmoretti Staff Lv 1

Looks like the issue with the ligand queue crash was also affecting the compound library search. I've adjusted a few things, and I think things are a bit better now.

You may (will) have to resubmit compounds to the library to take advantage of the fixed compound library search.