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Intermediate Overall Small Molecule DesignThis 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 starting compounds (these may get reordered to promote balanced sampling). - 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”.
100 pts.
19,727
First fun fact: most of these molecules are new, but weights 204.042, 262.357, 264.329, 271.263, 390.417, and 410.358 were also seen last week. (Edit: missed a couple of the repeats on the first draft.)
No crashes, went all the way through the ligand queue from 2 to 31 without a problem.
Compound 390.417 had a problem with not getting its bonus last week, but seems OK this week.
All 30 compounds received instant compound library results. Perhaps someone got there before I did?
Updated, here are the properties for the 30 compounds. The weight of compound 388.371 has been corrected, along with a couple of the cLogP values, which had small errors. The entire table is now in ascending molecular weight order. The aromatic and aliphatic ring counts have been dropped to improve the formatting. The "#" column has also been dropped.
The weights shown in bold indicate the compounds that were also seen in last week's puzzle 2363.
| weight | cLogP | PSA | heavy atoms | H-bond donors | H-bond acceptors | rotatable bonds |
|---|---|---|---|---|---|---|
| 204.042 | 2.62990 | 12.03 | 10 | 1 | 1 | 1 |
| 228.049 | 1.21270 | 61.80 | 12 | 2 | 4 | 1 |
| 245.246 | 0.33542 | 121.67 | 18 | 4 | 8 | 2 |
| 262.357 | 2.59240 | 51.45 | 19 | 1 | 5 | 7 |
| 264.329 | 1.00380 | 76.02 | 19 | 2 | 6 | 5 |
| 271.263 | 2.19384 | 59.16 | 19 | 1 | 4 | 4 |
| 274.328 | 0.62800 | 78.96 | 20 | 2 | 7 | 4 |
| 283.335 | 0.86780 | 67.07 | 21 | 1 | 6 | 2 |
| 295.330 | 1.95472 | 54.02 | 19 | 2 | 4 | 7 |
| 298.350 | 1.70870 | 105.64 | 22 | 4 | 7 | 4 |
| 307.741 | 1.29562 | 76.30 | 21 | 1 | 7 | 1 |
| 308.341 | 2.09300 | 88.00 | 23 | 2 | 6 | 6 |
| 315.285 | 1.23150 | 110.38 | 23 | 2 | 8 | 5 |
| 318.417 | 2.04260 | 74.61 | 23 | 3 | 5 | 5 |
| 320.241 | 3.31220 | 40.54 | 19 | 1 | 3 | 3 |
| 321.383 | 2.40492 | 74.08 | 21 | 0 | 6 | 4 |
| 327.356 | 2.80300 | 88.84 | 22 | 3 | 5 | 2 |
| 327.402 | 0.78030 | 76.07 | 22 | 1 | 6 | 3 |
| 330.413 | 1.77840 | 92.08 | 23 | 3 | 6 | 3 |
| 330.772 | 0.27110 | 95.60 | 22 | 1 | 8 | 9 |
| 340.387 | 2.57370 | 100.80 | 25 | 1 | 8 | 7 |
| 361.190 | 2.28320 | 58.12 | 21 | 1 | 5 | 2 |
| 378.450 | 1.77380 | 103.78 | 26 | 2 | 7 | 10 |
| 388.371 | 1.41260 | 104.81 | 26 | 2 | 7 | 7 |
| 389.431 | 3.02362 | 63.91 | 27 | 0 | 6 | 5 |
| 390.417 | 1.32140 | 118.32 | 27 | 2 | 8 | 8 |
| 408.437 | 1.98942 | 114.93 | 30 | 4 | 8 | 8 |
| 410.358 | 2.69010 | 40.62 | 28 | 0 | 4 | 6 |
| 432.455 | 4.35330 | 73.51 | 32 | 0 | 7 | 6 |
| 449.532 | 4.74300 | 80.59 | 32 | 1 | 7 | 4 |
Compounds with weights 308.341 and 327.402 also appear in puzzle 2360, but they are chemically different than the ones in this puzzle.
Updated, here the SMILES and chemical formulas for this week's ligand queue. The formula for one of the compounds has been corrected. The entire table is now sorted in order of ascending weight. The weights shown in bold are the compounds that also appeared in puzzle 2363. And somehow, the formatting now works.
Another update, the SMILES and formula for 378.450 have been corrected.
| weight | SMILES | formula |
|---|---|---|
| 204.042 | CNc1c(F)cccc1Br |
C7H7BrFN |
| 228.049 | OCc1nc2ncc(Br)cc2[nH]1 |
C7H6BrN3O |
| 245.246 | Cc1cc(Cn2cnc3c(N)nc(N)nc32)on1 |
C10H11N7O |
| 262.357 | CCC(CC)C(CNc1cccc2nncn12)OC |
C14H22N4O |
| 264.329 | CC(C)Cn1cc(NC(=O)C2CCNC(=O)C2)cn1 |
C13H20N4O2 |
| 271.263 | Cc1cc(C(=O)OCC2CC(F)(F)C2)c(=O)[nH]c1C |
C13H15F2NO3 |
| 274.328 | c1nc(NC[C@H]2Cn(C3CC3)CCO2)c2nc[nH]c2n1 |
C13H18N6O |
| 283.335 | OC1C2CC3CN(c4cncc(-n5cccn5)n4)C1C3C2 |
C15H17N5O |
| 295.330 | Cc1cnc(C(C)(C)NCC(=O)NCC(F)(F)F)s1 |
C11H16F3N3OS |
| 298.350 | Nc1n[nH]c2cc(-c3cn(CCC4(O)CCC4)nn3)ccc12 |
C15H18N6O |
| 307.741 | Cc1nn2c(c1O)CN(c1nc(Cl)nc3c1CCO3)CC2 |
C13H14ClN5O2 |
| 308.341 | O=C(NCCCc1ccncc1)c1ccc2ccnc(O)c2n1 |
C17H16N4O2 |
| 315.285 | O=C1Nc2ccc(C(=O)OCCc3cnc(=O)[nH]c3)cc2CO1 |
C15H13N3O5 |
| 318.417 | OC(CNc1cccc(C2(O)CCOC2)n1)C12CCC(CC1)C2 |
C18H26N2O3 |
| 320.241 | CSc1cc(C(=O)N2CCC(C)(O)C2)c(Cl)cc1Cl |
C13H15Cl2NO2S |
| 321.383 | Cc1ccc(S(=O)(=O)Oc2cccc(-n3cncn3)c2)s1 |
C13H11N3O3S2 |
| 327.356 | NS(=O)c1c[nH]c2ncc(C=C3CCC(F)(F)CC3)CC12 |
C13H15Cl2NO2S |
| 327.402 | CN([C@@H]1COC[C@H]1O)S(=O)(=O)c1cccc2c1OC(C)(C)C2 |
C15H21NO5S |
| 330.413 | CC1CCc2c(C(=O)N3Cc4n[nH]cc4C3C(N)=O)csc2C1 |
C16H18N4O2S |
| 330.772 | COC(=O)CN(C)C(=O)CCCN(C)c1cc(Cl)[nH]c(=O)n1 |
C13H19ClN4O4 |
| 340.387 | CC(C)c1cccc(N(C)C(=O)CCc2nc(-c3nnc[nH]3)no2)c1 |
C17H20N6O2 |
| 361.190 | O=C1CC2(CCCN(c3ncnc(C(F)F)c3Br)C2)CN1 |
C13H15BrF2N4O |
| 378.450 | CCCC(NC(=O)C(CCSC)N1C(=O)c2ccccc2c1=O)C(=O)O |
C18H28N2O5 |
| 388.371 | O=C(CS(=O)(=O)c1nc(-c2ccc3c(c2)CCC3)n[nH]1)NCC(F)(F)F |
C15H15F3N4O3S |
| 389.431 | Cc1ncc(-n2nc(Cc3ccc(F)cc3F)nc2CN2CCCC2=O)s1 |
C18H17F2N5OS |
| 390.417 | O=C(C=Cc1ccc[nH]1)O[C@H]1CS(=O)(=O)C[C@@H]1OC(=O)C=Cc1ccc[nH]1 |
C18H18N2O6S |
| 408.437 | Cc1cc(C(=O)NC2(CNC(=O)c3ccc(N)nc3)CC2)nn1-c1ccccc1F |
C21H21FN6O2 |
| 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 |
| 432.455 | Fc1ccc(COc2ccccc2-c2nnc(-c3ccc(N4CCOCC4)nc3)o2)cc1 |
C24H21FN4O3 |
| 449.532 | O=c1[nH]c(CN2CCCC2c2ccc3c(c2)OCCO3)nc2scc(-c3ccco3)c12 |
C23H21N3O4S |
Compounds with weights 308.341 and 327.402 also appear in puzzle 2360, but they are chemically different than the ones in this puzzle.
The formatting has improved, but these tables are still kind of awkward. You can copy them and paste into a spreadsheet. It's a little tricky getting an exact selection, but not too bad.
If you're copying a singles SMILES string, watch out for trailing spaces. Jmol doesn't handle trailing spaces correctly, but other tools may be smart enough to trim any whitespace.
I also created wiki versions of the tables above. The wiki tables have sortable columns.
Edit: puzzle 2360 had compounds with weights 308.341 and 327.402. Puzzle 2366 has two different compounds with the same weights. There may be additional cases of "same weight, different compound". A revised and expanded table will be available soon.
Edit: corrected version, the 2366 column was wrong in the previous version. A second correction adjusts the counts to 2363 and 2363 to reflect the inclusion of 411.414 in this list.
Just in case you haven't had enough tables, here's one suggested by jeff101. It shows all the compounds seen in 2360, 2363, and 2366. The starter compound 411.414 is included.
Many compounds have appeared in more than one puzzle. For example, 271.263 and 390.417 have appeared in all three puzzles. (And yes, so has 411.414.)
| weight | In 2360? | In 2363? | In 2366? |
|---|---|---|---|
| 204.042 | Y | Y | |
| 218.300 | Y | ||
| 228.049 | Y | ||
| 231.215 | Y | ||
| 245.246 | Y | ||
| 246.314 | Y | ||
| 258.296 | Y | ||
| 262.357 | Y | Y | Y |
| 264.329 | Y | Y | |
| 271.263 | Y | Y | Y |
| 274.328 | Y | Y | |
| 281.337 | Y | ||
| 283.335 | Y | ||
| 290.319 | Y | ||
| 291.250 | Y | ||
| 292.295 | Y | ||
| 295.330 | Y | ||
| 297.366 | Y | ||
| 298.318 | Y | ||
| 298.350 | Y | ||
| 299.274 | Y | ||
| 306.395 | Y | ||
| 307.741 | Y | ||
| 308.341 | Y | Y | |
| 313.327 | Y | ||
| 314.338 | Y | ||
| 315.285 | Y | ||
| 315.356 | Y | ||
| 317.389 | Y | ||
| 317.393 | Y | ||
| 318.381 | Y | ||
| 318.417 | Y | ||
| 320.241 | Y | ||
| 321.383 | Y | ||
| 323.260 | Y | ||
| 327.356 | Y | ||
| 327.402 | Y | Y | |
| 328.368 | Y | ||
| 330.413 | Y | ||
| 330.772 | Y | ||
| 335.404 | Y | ||
| 340.387 | Y | ||
| 342.421 | Y | ||
| 343.261 | Y | ||
| 343.361 | Y | ||
| 347.375 | Y | ||
| 351.762 | Y | ||
| 361.190 | Y | ||
| 366.450 | Y | ||
| 368.210 | Y | ||
| 368.449 | Y | ||
| 368.481 | Y | ||
| 368.484 | Y | ||
| 369.769 | Y | ||
| 376.428 | Y | ||
| 378.450 | Y | Y | |
| 380.426 | Y | ||
| 382.825 | Y | ||
| 385.445 | Y | ||
| 385.552 | Y | ||
| 388.371 | Y | ||
| 388.424 | Y | ||
| 389.431 | Y | ||
| 390.417 | Y | Y | Y |
| 391.262 | Y | ||
| 396.245 | Y | ||
| 400.258 | Y | ||
| 408.437 | Y | ||
| 410.358 | Y | Y | |
| 411.414 | Y | Y | Y |
| 419.428 | Y | ||
| 421.457 | Y | ||
| 426.401 | Y | ||
| 432.455 | Y | ||
| 433.512 | Y | ||
| 449.532 | Y | ||
| 451.918 | Y | ||
| 77 | 30 | 31 | 31 |
Still better yet, the wiki now has a complete list with all the properties of all the ligand queue compounds in one big table:
https://foldit.fandom.com/wiki/CACHE_SARS_Nsp3_Reranking_challenge_ligand_queue_properties
