Submission Details

Molecule(s):
Cc1nc(SCC(=O)C2CC2)c(C#N)c(C)c1C

MAR-TRE-14ce9fd6-2

Cc1nc(SCC(=O)C2CC2)c(C#N)c(C)c1C

CC(Sc1nc2c(cc1C#N)CCCCC2)C(=O)O

MAR-TRE-14ce9fd6-5

CC(Sc1nc2c(cc1C#N)CCCCC2)C(=O)O

N#Cc1cc2c(nc1SCC(=O)Nc1ccc(S(N)(=O)=O)cc1)CCCCC2

MAR-TRE-14ce9fd6-6

N#Cc1cc2c(nc1SCC(=O)Nc1ccc(S(N)(=O)=O)cc1)CCCCC2

N#Cc1cc2c(nc1SCC(=O)Nc1ccc(S(N)(=O)=O)cc1)CCCC2

MAR-TRE-14ce9fd6-7

N#Cc1cc2c(nc1SCC(=O)Nc1ccc(S(N)(=O)=O)cc1)CCCC2

N#Cc1ccc(CSc2nnc(COc3ccccc3)o2)cc1

MAR-TRE-14ce9fd6-8

N#Cc1ccc(CSc2nnc(COc3ccccc3)o2)cc1

COc1ccc(-c2nnc(SCc3ccc(C#N)cc3)o2)cc1

MAR-TRE-14ce9fd6-9

COc1ccc(-c2nnc(SCc3ccc(C#N)cc3)o2)cc1

Cn1c(SCc2cccc(C#N)c2)nc2sc3c(c2c1=O)CCC3

MAR-TRE-14ce9fd6-10

Cn1c(SCc2cccc(C#N)c2)nc2sc3c(c2c1=O)CCC3

CCS(=O)(=O)CCSc1nc2c(cc1C#N)CCCC2

MAR-TRE-14ce9fd6-11

CCS(=O)(=O)CCSc1nc2c(cc1C#N)CCCC2

N#Cc1ccc(CSc2nc3ccccc3c(=O)[nH]2)cc1

MAR-TRE-14ce9fd6-13

N#Cc1ccc(CSc2nc3ccccc3c(=O)[nH]2)cc1

CC1(C)CC(=O)c2cc(C#N)c(SCC(N)=O)nc2C1

MAR-TRE-14ce9fd6-15

CC1(C)CC(=O)c2cc(C#N)c(SCC(N)=O)nc2C1

Cc1sc2nc(SCc3cccc(C#N)c3)n(C)c(=O)c2c1C

MAR-TRE-14ce9fd6-16

Cc1sc2nc(SCc3cccc(C#N)c3)n(C)c(=O)c2c1C

N#Cc1ccc(CSc2nc3c(c(=O)[nH]2)CCCC3)cc1

MAR-TRE-14ce9fd6-21

N#Cc1ccc(CSc2nc3c(c(=O)[nH]2)CCCC3)cc1

Cc1cc(C)c(C#N)c(SCc2ccc3c(c2)OCO3)n1

MAR-TRE-14ce9fd6-23

Cc1cc(C)c(C#N)c(SCc2ccc3c(c2)OCO3)n1

N#Cc1ccc(CSc2nc3ccccc3o2)c(Cl)c1

MAR-TRE-14ce9fd6-24

N#Cc1ccc(CSc2nc3ccccc3o2)c(Cl)c1

Cn1c(SCc2cccc(C#N)c2)nc2ccccc2c1=O

MAR-TRE-14ce9fd6-25

Cn1c(SCc2cccc(C#N)c2)nc2ccccc2c1=O

Cc1ccc(NC(=O)CSc2ncccc2C#N)cc1C

MAR-TRE-14ce9fd6-27

Cc1ccc(NC(=O)CSc2ncccc2C#N)cc1C

COc1ccc(-c2nnc(SCc3cccc(C#N)c3)o2)cc1

MAR-TRE-14ce9fd6-28

COc1ccc(-c2nnc(SCc3cccc(C#N)c3)o2)cc1

N#Cc1ccc(CSc2nc3c(c(=O)[nH]2)CCC3)cc1

MAR-TRE-14ce9fd6-33

N#Cc1ccc(CSc2nc3c(c(=O)[nH]2)CCC3)cc1

N#Cc1ccc(CSc2nnc(-c3ccccc3)o2)cc1

MAR-TRE-14ce9fd6-34

N#Cc1ccc(CSc2nnc(-c3ccccc3)o2)cc1

Cc1nc(SCc2ccc(C#N)cc2)nc2c1CCCC2

MAR-TRE-14ce9fd6-35

Cc1nc(SCc2ccc(C#N)cc2)nc2c1CCCC2

N#Cc1c(NC(=O)CSc2ccccn2)sc2c1CCCCC2

MAR-TRE-14ce9fd6-36

N#Cc1c(NC(=O)CSc2ccccn2)sc2c1CCCCC2

CSc1cccc(NC(=O)CSc2ncccc2C#N)c1

MAR-TRE-14ce9fd6-37

CSc1cccc(NC(=O)CSc2ncccc2C#N)c1

N#Cc1ccc(CSc2nc3ccc(Br)cc3[nH]2)cc1

MAR-TRE-14ce9fd6-38

N#Cc1ccc(CSc2nc3ccc(Br)cc3[nH]2)cc1

N#Cc1cc2c(nc1SCc1nc3ccccc3[nH]1)CCC2

MAR-TRE-14ce9fd6-40

N#Cc1cc2c(nc1SCc1nc3ccccc3[nH]1)CCC2

Cc1cc(-c2ccccc2)nc(SCc2ccc(C#N)cc2)n1

MAR-TRE-14ce9fd6-41

Cc1cc(-c2ccccc2)nc(SCc2ccc(C#N)cc2)n1

CCC1CCc2c(sc(NC(=O)CCC(=O)O)c2C#N)C1

MAR-TRE-14ce9fd6-45

CCC1CCc2c(sc(NC(=O)CCC(=O)O)c2C#N)C1

Cc1cc(SCc2ccc(C#N)cc2)nc2ccccc12

MAR-TRE-14ce9fd6-47

Cc1cc(SCc2ccc(C#N)cc2)nc2ccccc12

N#Cc1ccc(-c2ccccc2)nc1SCc1ccc(C(=O)O)cc1

MAR-TRE-14ce9fd6-48

N#Cc1ccc(-c2ccccc2)nc1SCc1ccc(C(=O)O)cc1

Cc1cc(C)c(C#N)c(SCc2ccc(C(=O)O)cc2)n1

MAR-TRE-14ce9fd6-50

Cc1cc(C)c(C#N)c(SCc2ccc(C(=O)O)cc2)n1

Cc1sc(NC(=O)CCCC(=O)O)c(C#N)c1C

MAR-TRE-14ce9fd6-56

Cc1sc(NC(=O)CCCC(=O)O)c(C#N)c1C

Cc1cc(C)c(C#N)c(SCc2ccc(Cl)nc2)n1

MAR-TRE-14ce9fd6-57

Cc1cc(C)c(C#N)c(SCc2ccc(Cl)nc2)n1

Cn1c(SCc2ccc(C#N)cc2Cl)nc2ccccc21

MAR-TRE-14ce9fd6-58

Cn1c(SCc2ccc(C#N)cc2Cl)nc2ccccc21

Cc1ccc(C#N)c(SCc2ccc(C(=O)O)cc2)n1

MAR-TRE-14ce9fd6-65

Cc1ccc(C#N)c(SCc2ccc(C(=O)O)cc2)n1

Cc1nn(-c2nc3ccccc3s2)c(O)c1CCC#N

MAR-TRE-14ce9fd6-66

Cc1nn(-c2nc3ccccc3s2)c(O)c1CCC#N

N#Cc1c(NC(=O)CSc2ncn(-c3ccccc3)n2)sc2c1CCCC2

MAR-TRE-14ce9fd6-67

N#Cc1c(NC(=O)CSc2ncn(-c3ccccc3)n2)sc2c1CCCC2

CCOC(=O)C(=O)Nc1sc2c(c1C#N)CCC(C)C2

MAR-TRE-14ce9fd6-69

CCOC(=O)C(=O)Nc1sc2c(c1C#N)CCC(C)C2

N#Cc1c(NC(=O)CCC(=O)O)sc2c1CCCCC2

MAR-TRE-14ce9fd6-71

N#Cc1c(NC(=O)CCC(=O)O)sc2c1CCCCC2

N#Cc1ccc(CSc2nc(-c3ccccc3)cc(=O)[nH]2)cc1

MAR-TRE-14ce9fd6-73

N#Cc1ccc(CSc2nc(-c3ccccc3)cc(=O)[nH]2)cc1

CC(C)(C)c1cc(CCCC#N)cc(C(C)(C)C)c1O

MAR-TRE-14ce9fd6-74

CC(C)(C)c1cc(CCCC#N)cc(C(C)(C)C)c1O

COc1ccc(CSc2nc(C)cc(C)c2C#N)cc1

MAR-TRE-14ce9fd6-77

COc1ccc(CSc2nc(C)cc(C)c2C#N)cc1

CCCC1CCc2c(sc(NC(=O)CCC(=O)O)c2C#N)C1

MAR-TRE-14ce9fd6-82

CCCC1CCc2c(sc(NC(=O)CCC(=O)O)c2C#N)C1

CC(=O)c1cc(CSc2nc(-c3cccs3)ccc2C#N)cs1

MAR-TRE-14ce9fd6-83

CC(=O)c1cc(CSc2nc(-c3cccs3)ccc2C#N)cs1

N#CC1C(c2ccsc2)C(C(N)=O)C(=O)NC1(O)c1ccccc1

MAR-TRE-14ce9fd6-85

N#CC1C(c2ccsc2)C(C(N)=O)C(=O)NC1(O)c1ccccc1

COc1cccc(CSc2nc3c(cc2C#N)CCC3)c1

MAR-TRE-14ce9fd6-90

COc1cccc(CSc2nc3c(cc2C#N)CCC3)c1

COc1cccc(CSc2nc3c(cc2C#N)CCCCC3)c1

MAR-TRE-14ce9fd6-93

COc1cccc(CSc2nc3c(cc2C#N)CCCCC3)c1

N#Cc1cccc(OCc2ccc(Cl)c(Cl)c2)c1

MAR-TRE-14ce9fd6-97

N#Cc1cccc(OCc2ccc(Cl)c(Cl)c2)c1


Design Rationale:

A nitrile group is an attractive covalent bonding warhead for cysteine proteases because the proximity of the HIS(41) residue facilitating the formation of the SG-C(=N-H)R binding complex. Selectivity is then possible by non-covalent interactions elsewhere in the binding site. This selection of 500 molecules from nearly 8,000 commercially available nitriles in the ChemBridge Express Pick collection are predicted to bind using the THINK software (https://treweren.com) into the 6WNP crystal structure (which has a slightly more favourable geometry than 5RF7). These hits were partitioned by lipophilicity (as calculated by the software) in to 5 sets. This is set 5 of 5.

Other Notes:

A SD file of the 3D binding coordinates is available.

Discussion: