COVID Moonshot Sprint 9 for P1 pocket replacement based on x10959 (ADA-UCB-6c2cb422-1) to optimize substituents in the P1 pocket with Mpro dimer and neutral Cys145:His41 catalytic dyad
| Rank | Compound | SMILES | ΔG / kcal mol-1 | pIC50 | |
|---|---|---|---|---|---|
| 1 | JAN-GHE-f4ca5a00-18 |
|
CCCCC(c1cccc(c1)Cl)C(=O)Nn2cncc2C3CC3 | −12.0 ± 0.2 | 8.7 ± 0.1 |
| 2 | JAN-GHE-f4ca5a00-20 |
|
CCCCC(c1cccc(c1)Cl)C(=O)Nn2c(cnn2)C3CC3 | −11.7 ± 0.1 | 8.51 ± 0.08 |
| 3 | BAR-COM-0f94fc3d-24 |
|
c1ccc2c(c1)ncn2NC(=O)C(c3cccc(c3)Cl)(F)F | −10.66 ± 0.09 | 7.76 ± 0.07 |
| 4 | EDJ-MED-97c1bf5c-2 |
|
COc1c(c2nnnn2cn1)NC(=O)Cc3cccc(c3)Cl | −10.5 ± 0.1 | 7.64 ± 0.08 |
| 5 | EDJ-MED-c8e7a002-7 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2c3nncn3cnc2Cl | −10.5 ± 0.1 | 7.62 ± 0.08 |
| 6 | JAN-GHE-83b26c96-15 |
|
Cc1ccncc1N(C)C(=O)Cc2cccc(c2)Cl | −10.36 ± 0.09 | 7.55 ± 0.07 |
| 7 | JAN-GHE-5a013bed-8 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cnccn2 | −10.4 ± 0.1 | 7.54 ± 0.08 |
| 8 | EDG-MED-0da5ad92-1 |
|
Cc1ccncc1N(C)C(=O)Cc2cccc(c2)Cl | −10.23 ± 0.10 | 7.45 ± 0.07 |
| 9 | EDJ-MED-c8e7a002-8 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2c3nnnn3cnc2Cl | −10.2 ± 0.1 | 7.41 ± 0.08 |
| 10 | MIC-UNK-67d4a29a-1 |
|
CN(c1cncc2c1c(ccc2)Cl)C(=O)Cc3cccc(c3)Cl | −10.1 ± 0.1 | 7.4 ± 0.1 |
| 11 | MAT-POS-bb423b95-8 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncc3c2ccc(c3)O | −10.10 ± 0.08 | 7.36 ± 0.06 |
| 12 | DAR-DIA-076fb6ea-10 |
|
Cc1ccncc1N(C#CC2CCCN2)C(=O)Cc3cccc(c3)Cl | −10.1 ± 0.1 | 7.32 ± 0.08 |
| 13 | PET-UNK-1320d94d-22 |
|
CN(C)C(=O)[C@H]1CC[C@H](O1)C(=O)N(C)[C@@H](c2cccc(c2)Cl)C(=O)Nc3cncc4c3cccc4 | −10.0 ± 0.2 | 7.3 ± 0.1 |
| 14 | MAK-UNK-ffc90da7-3 |
|
CC(C)OCC(c1ccc2c(c1)cncc2NC(=O)Cc3cccc(c3)Cl)NC | −9.92 ± 0.09 | 7.22 ± 0.07 |
| 15 | JAN-GHE-f4ca5a00-17 |
|
c1cc(cc(c1)Cl)CC(=O)Nn2c(cnn2)C3CC3 | −9.80 ± 0.09 | 7.14 ± 0.06 |
| 16 | MIC-UNK-67d4a29a-4 |
|
CN(c1cncc2c1c(ccc2)OC)C(=O)Cc3cccc(c3)Cl | −9.7 ± 0.1 | 7.1 ± 0.1 |
| 17 | EDJ-MED-076d6e64-1 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncn3c2nnc3 | −9.68 ± 0.09 | 7.05 ± 0.06 |
| 18 | BAR-COM-ebf5acce-11 |
|
Cc1ccncc1N(C[C@@]2(CCOC2)O)C(=O)Cc3cccc(c3)Cl | −9.6 ± 0.2 | 7.0 ± 0.1 |
| 19 | BEN-DND-1e24cf73-4 |
|
COc1ccccc1n2cncc2NC(=O)Cc3cccc(c3)Cl | −9.6 ± 0.1 | 6.97 ± 0.09 |
| 20 | JAN-GHE-5a013bed-4 |
|
c1cc(cc(c1)Cl)CC(=O)Nn2cn[nH]c2=O | −9.6 ± 0.1 | 6.96 ± 0.09 |
| 21 | TRY-UNI-9f475305-3 |
|
Cc1ccncc1NC(=O)C(c2cccc(c2)Cl)c3nnc(s3)C | −9.45 ± 0.09 | 6.88 ± 0.07 |
| 22 | JOH-UNI-a38a7bdd-7 |
|
Cc1ccncc1N(C(=O)Cc2cccc(c2)Cl)C(=O)C3CC3C(F)(F)F | −9.38 ± 0.10 | 6.84 ± 0.07 |
| 23 | MIC-UNK-c66144cb-3 |
|
c1ccc2c(c1)cncc2NC(=O)C(CCC3CCCCC3)c4cccc(c4)Cl | −9.3 ± 0.2 | 6.8 ± 0.1 |
| 24 | ALP-POS-3b848b35-4 |
|
c1ccc2c(c1)cncc2NC(=O)C(CCC3CCCCC3)c4cccc(c4)Cl | −9.3 ± 0.2 | 6.8 ± 0.1 |
| 25 | JOH-UNI-ee5ed7c8-7 |
|
CN(c1cncc2c1cccc2)C(=O)C(CC#N)c3cccc(c3)Cl | −9.3 ± 0.1 | 6.78 ± 0.08 |
| 26 | PET-UNK-12d8d43f-2 |
|
COC(=O)N(c1cncc2c1cccc2)C(=O)Cc3cccc(c3)Cl | −9.3 ± 0.1 | 6.76 ± 0.08 |
| 27 | JIN-POS-6dc588a4-16 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2c3ccncc3on2 | −9.25 ± 0.09 | 6.74 ± 0.06 |
| 28 | JOH-UNI-3fc3434e-7 |
|
CN(c1cncc2c1cccc2)C(=O)C(CC#N)c3cccc(c3)Cl | −9.2 ± 0.1 | 6.7 ± 0.1 |
| 29 | MIC-UNK-c66144cb-1 |
|
c1ccc2c(c1)cncc2NC(=O)C(CCc3cccc(c3)F)c4cccc(c4)Cl | −9.2 ± 0.1 | 6.70 ± 0.09 |
| 30 | PET-UNK-1320d94d-6 |
|
c1ccc2c(c1)cncc2NC(=O)[C@H](c3cccc(c3)Cl)NC(=O)[C@@H]4CC[C@@H](O4)C(=O)N5CCC5 | −9.2 ± 0.2 | 6.7 ± 0.1 |
| 31 | PET-UNK-5ecb6237-1 |
|
c1ccc2c(c1)cncc2N(C#N)C(=O)Cc3cccc(c3)Cl | −9.12 ± 0.09 | 6.65 ± 0.07 |
| 32 | DAR-DIA-076fb6ea-6 |
|
Cc1ccncc1N(C#CC#N)C(=O)Cc2cccc(c2)Cl | −9.07 ± 0.09 | 6.61 ± 0.07 |
| 33 | MIC-UNK-c66144cb-2 |
|
c1ccc2c(c1)cncc2NC(=O)C(CCc3ccc(cc3)F)c4cccc(c4)Cl | −9.0 ± 0.1 | 6.58 ± 0.09 |
| 34 | PET-UNK-6314f867-2 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncc3c2ccc(c3)C#N | −8.97 ± 0.08 | 6.54 ± 0.06 |
| 35 | PET-UNK-b38839dc-2 |
|
COc1cc2c(cc1Cl)cncc2NC(=O)Cc3cccc(c3)Cl | −8.95 ± 0.10 | 6.52 ± 0.07 |
| 36 | MAT-POS-f7918075-7 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncc3c2CC(=O)N3 | −8.91 ± 0.09 | 6.49 ± 0.07 |
| 37 | BEN-DND-1e24cf73-2 |
|
Cc1ccccc1n2cncc2NC(=O)Cc3cccc(c3)Cl | −8.9 ± 0.1 | 6.46 ± 0.08 |
| 38 | JAN-GHE-f4ca5a00-19 |
|
CCCCC(c1cccc(c1)Cl)C(=O)Nn2cnnc2C3CC3 | −8.8 ± 0.2 | 6.4 ± 0.1 |
| 39 | JAN-GHE-5a013bed-9 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncnc2 | −8.83 ± 0.09 | 6.43 ± 0.06 |
| 40 | MAT-POS-199e2e7c-2 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2c3cn[nH]c3ccn2 | −8.8 ± 0.1 | 6.39 ± 0.08 |
| 41 | JAN-GHE-5a013bed-5 |
|
c1cc(cc(c1)Cl)CC(=O)Nn2cnnc2 | −8.7 ± 0.1 | 6.32 ± 0.09 |
| 42 | JOH-UNI-3fc3434e-6 |
|
c1ccc2c(c1)cncc2NC(=O)C(CC#N)c3cccc(c3)Cl | −8.6 ± 0.1 | 6.30 ± 0.08 |
| 43 | JAN-GHE-f4ca5a00-14 |
|
c1cc(cc(c1)Cl)CC(=O)Nn2cncc2C3CC3 | −8.6 ± 0.1 | 6.28 ± 0.09 |
| 44 | MIC-UNK-d935700b-1 |
|
Cc1c(cn[nH]c1=O)NC(=O)Cc2cccc(c2)Cl | −8.6 ± 0.1 | 6.25 ± 0.08 |
| 45 | PET-UNK-158bee2a-4 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2ncns2 | −8.58 ± 0.10 | 6.25 ± 0.07 |
| 46 | JAN-GHE-5a013bed-1 |
|
Cc1c(n(nn1)NC(=O)Cc2cccc(c2)Cl)C | −8.56 ± 0.06 | 6.23 ± 0.05 |
| 47 | MIC-UNK-5a93dd5f-4 |
|
CC(=O)NC1CCN(CC1)C(c2cccc(c2)Cl)C(=O)Nc3cncc4c3cccc4 | −8.6 ± 0.4 | 6.2 ± 0.3 |
| 48 | PET-UNK-1320d94d-2 |
|
CN(C)C(=O)[C@H]1CC[C@H](O1)C(=O)N[C@@H](c2cccc(c2)Cl)C(=O)Nc3cncc4c3cccc4 | −8.6 ± 0.2 | 6.2 ± 0.1 |
| 49 | ADA-UNI-f8e79267-7 |
|
CS(=O)(=O)NCCOC(c1cccc(c1)Cl)C(=O)Nc2cccnc2 | −8.6 ± 0.1 | 6.23 ± 0.08 |
| 50 | ALP-POS-95b75b4d-6 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cnccc2O | −8.52 ± 0.10 | 6.21 ± 0.07 |
| 51 | MAK-UNK-c749d764-6 |
|
CC(CNCCCO)C(c1cccc(c1)Cl)C(=O)Nc2cncc3c2cccc3 | −8.5 ± 0.2 | 6.2 ± 0.2 |
| 52 | RUB-POS-1325a9ea-14 |
|
Cn1c2c(cncc2NC(=O)Cc3cccc(c3)Cl)cn1 | −8.49 ± 0.07 | 6.19 ± 0.05 |
| 53 | PET-UNK-1320d94d-7 |
|
c1ccc2c(c1)cncc2NC(=O)[C@@H](c3cccc(c3)Cl)NC(=O)[C@@H]4C[C@@H](O4)C(=O)N5CCCC5 | −8.5 ± 0.2 | 6.2 ± 0.1 |
| 54 | EDG-MED-0da5ad92-14 |
|
Cc1c(cccn1)NC(=O)Cc2cccc(c2)Cl | −8.5 ± 0.1 | 6.16 ± 0.09 |
| 55 | MIC-UNK-67d4a29a-3 |
|
Cc1cccc2c1c(cnc2)N(C)C(=O)Cc3cccc(c3)Cl | −8.4 ± 0.2 | 6.1 ± 0.1 |
| 56 | JOH-UNI-ee5ed7c8-6 |
|
c1ccc2c(c1)cncc2NC(=O)C(CC#N)c3cccc(c3)Cl | −8.4 ± 0.1 | 6.13 ± 0.08 |
| 57 | MAK-UNK-ffc90da7-4 |
|
CC(CNCC1CCCO1)C(c2cccc(c2)Cl)C(=O)Nc3cncc4c3cccc4 | −8.4 ± 0.3 | 6.1 ± 0.2 |
| 58 | MIC-UNK-d36ab305-1 |
|
CC(=O)Nc1ccc(cc1)C(c2cccc(c2)Cl)C(=O)Nc3cncc4c3cccc4 | −8.3 ± 0.1 | 6.1 ± 0.1 |
| 59 | ALP-POS-3fc1724e-8 |
|
c1ccc2c(c1)[nH]c(n2)NC(=O)C(CCC3CCCCC3)c4cccc(c4)Cl | −8.3 ± 0.2 | 6.1 ± 0.1 |
| 60 | MAK-UNK-ffc90da7-6 |
|
CC(CNCCCO)c1ccc2cncc(c2c1)NC(=O)Cc3cccc(c3)Cl | −8.34 ± 0.10 | 6.07 ± 0.07 |
| 61 | PET-UNK-f92d7c0c-2 |
|
c1ccc2c(c1)COC[C@@H]2NC(=O)Cc3cccc(c3)Cl | −8.3 ± 0.1 | 6.06 ± 0.08 |
| 62 | JOH-UNI-6fede743-5 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2c3cc(ccc3cnc2C(F)F)F | −8.3 ± 0.1 | 6.06 ± 0.09 |
| 63 | TRY-UNI-9f475305-8 |
|
Cc1cc(no1)CN(C(=O)C(C)c2cccc(c2)Cl)C(=O)NC3CC3 | −8.3 ± 0.1 | 6.0 ± 0.1 |
| 64 | JAN-GHE-83b26c96-7 |
|
Cc1c(cncn1)NC(=O)C(c2cccc(c2)Cl)C(C)C | −8.28 ± 0.09 | 6.03 ± 0.07 |
| 65 | TRY-UNI-714a760b-15 |
|
Cc1c(cncc1NC(=O)C(C)c2cccc(c2)Cl)N | −8.28 ± 0.07 | 6.03 ± 0.05 |
| 66 | EDJ-MED-c8e7a002-1 |
|
COc1ccc2c(c1)onc2NC(=O)Cc3cccc(c3)Cl | −8.3 ± 0.1 | 6.03 ± 0.10 |
| 67 | MAT-POS-f7918075-4 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncc3c2[nH]c(=O)[nH]3 | −8.26 ± 0.08 | 6.02 ± 0.06 |
| 68 | JAN-GHE-5a013bed-2 |
|
c1ccc2c(c1)ncn2NC(=O)Cc3cccc(c3)Cl | −8.25 ± 0.07 | 6.01 ± 0.05 |
| 69 | RUB-POS-1325a9ea-8 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncn3c2ncc3 | −8.24 ± 0.09 | 6.00 ± 0.07 |
| 70 | MIC-UNK-50cce87d-2 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncc3c2c(ccc3)Cl | −8.21 ± 0.08 | 5.98 ± 0.06 |
| 71 | SAM-UNK-2684b532-3 |
|
Cc1ccncc1NC(=O)C(c2cccc(c2)Cl)c3nnc(s3)C | −8.2 ± 0.1 | 5.96 ± 0.10 |
| 72 | PET-UNK-1320d94d-5 |
|
c1ccc2c(c1)cncc2NC(=O)[C@@H](c3cccc(c3)Cl)NC(=O)[C@@H]4CC[C@@H](O4)C(=O)N5CCC5 | −8.2 ± 0.2 | 6.0 ± 0.1 |
| 73 | MIC-UNK-67d4a29a-2 |
|
CN(c1cncc2c1c(ccc2)F)C(=O)Cc3cccc(c3)Cl | −8.2 ± 0.1 | 5.95 ± 0.09 |
| 74 | MIC-UNK-8971c93c-1 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncc3c2[nH]c(=O)[nH]3 | −8.15 ± 0.08 | 5.94 ± 0.06 |
| 75 | MAT-POS-bb423b95-1 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncc3c2ccnc3 | −8.14 ± 0.06 | 5.93 ± 0.05 |
| 76 | PET-UNK-f92d7c0c-9 |
|
CN([C@@H]1COCc2c1cccc2)C(=O)Cc3cccc(c3)Cl | −8.1 ± 0.1 | 5.93 ± 0.09 |
| 77 | MIC-UNK-7574fcc6-1 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncc3c2c(cc(c3)F)F | −8.12 ± 0.06 | 5.91 ± 0.05 |
| 78 | MIC-UNK-50cce87d-3 |
|
Cc1cccc2c1c(cnc2)NC(=O)Cc3cccc(c3)Cl | −8.11 ± 0.05 | 5.91 ± 0.04 |
| 79 | SAM-UNK-2684b532-1 |
|
Cc1ccncc1NC(=O)C(c2ccccc2)c3cccc(c3)Cl | −8.10 ± 0.09 | 5.90 ± 0.06 |
| 80 | JOH-UNI-50ce7ec3-4 |
|
c1ccc2c(c1)c(cnc2C(F)F)N(C(=O)Cc3cccc(c3)Cl)S(=O)(=O)F | −8.1 ± 0.3 | 5.9 ± 0.2 |
| 81 | MIC-UNK-5a93dd5f-12 |
|
c1ccc2c(c1)cncc2NC(=O)C(c3cccc(c3)Cl)N4CCC(C4)N5CCCCC5 | −8.1 ± 0.1 | 5.87 ± 0.09 |
| 82 | EDJ-MED-6e43a462-5 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cnc3n2ccnc3 | −8.0 ± 0.1 | 5.86 ± 0.09 |
| 83 | EDJ-MED-50fe53e8-1 |
|
c1ccc2c(c1)cnnc2NC(=O)Cc3cccc(c3)Cl | −8.00 ± 0.06 | 5.83 ± 0.05 |
| 84 | JOH-UNI-50ce7ec3-3 |
|
C=CS(=O)(=O)N(c1cnc(c2c1cccc2)C(F)F)C(=O)Cc3cccc(c3)Cl | −8.0 ± 0.2 | 5.8 ± 0.2 |
| 85 | PET-UNK-6314f867-3 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncc3c2c(ccc3)C#N | −7.9 ± 0.1 | 5.79 ± 0.08 |
| 86 | MIC-UNK-50cce87d-1 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncc3c2c(ccc3)F | −7.92 ± 0.06 | 5.77 ± 0.04 |
| 87 | MAK-UNK-c749d764-22 |
|
CC(CNCC1CCCO1)C(c2cccc(c2)Cl)C(=O)Nc3cncc4c3cccc4 | −7.9 ± 0.2 | 5.8 ± 0.1 |
| 88 | VLA-UNK-9a7dc93f-7 |
|
COC(c1cccc(c1)Cl)C(=O)Nc2cncc3c2cccc3 | −7.91 ± 0.08 | 5.76 ± 0.06 |
| 89 | BEN-DND-02317c5c-8 |
|
c1ccn2c(c1)nnc2NC(=O)Cc3cccc(c3)Cl | −7.88 ± 0.09 | 5.74 ± 0.07 |
| 90 | EDJ-MED-ee07cf00-12 |
|
c1ccc2c(c1)cncc2NC(=O)C(c3cccc(c3)Cl)NC(=O)COc4ccc(cc4)C(=O)N | −7.87 ± 0.09 | 5.73 ± 0.06 |
| 91 | BAR-COM-0f94fc3d-38 |
|
CCC(c1cccc(c1)Cl)(C(=O)Nc2cnccc2C)O | −7.9 ± 0.1 | 5.73 ± 0.07 |
| 92 | JAN-GHE-5a013bed-7 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2nncs2 | −7.86 ± 0.09 | 5.73 ± 0.06 |
| 93 | ADA-UCB-6c2cb422-11 |
|
COc1ccccc1CO[C@@H](c2cccc(c2)Cl)C(=O)Nc3cc(=O)[nH]c4c3cccc4 | −7.9 ± 0.2 | 5.7 ± 0.1 |
| 94 | PET-UNK-b1ef24dc-2 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncc3c2snc3 | −7.85 ± 0.07 | 5.72 ± 0.05 |
| 95 | AGN-NEW-c7b24fe3-4 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cccnc2C#N | −7.84 ± 0.09 | 5.71 ± 0.07 |
| 96 | MIC-UNK-13557a72-1 |
|
c1cc(cc(c1)Cl)CC(=O)NC2CN3CCC2CC3 | −7.82 ± 0.09 | 5.70 ± 0.07 |
| 97 | JAG-UCB-a3ef7265-10 |
|
Cc1nnc(s1)NC(=O)Cc2cccc(c2F)Cl | −7.8 ± 0.1 | 5.69 ± 0.08 |
| 98 | JOH-UNI-3fc3434e-3 |
|
c1cc(cc(c1)Cl)CC(=O)Nc2cncc3c2c(ccc3)CC(F)(F)F | −7.8 ± 0.1 | 5.65 ± 0.09 |
| 99 | EDG-MED-0da5ad92-5 |
|
Cc1ccncc1NC(=O)C(CO)c2cccc(c2)Cl | −7.75 ± 0.10 | 5.65 ± 0.07 |
| 100 | AGN-NEW-c7b24fe3-5 |
|
C#Cc1c(cccn1)NC(=O)Cc2cccc(c2)Cl | −7.75 ± 0.10 | 5.65 ± 0.07 |