Submission Details

Molecule(s):
Cc1cc(NC(=O)CSc2nc3c(cc2C#N)CCCCC3)no1

MAR-TRE-1c920f6f-1

Cc1cc(NC(=O)CSc2nc3c(cc2C#N)CCCCC3)no1

N#CCSc1nc(S(=O)(=O)c2ccccc2)c(Cl)s1

MAR-TRE-1c920f6f-2

N#CCSc1nc(S(=O)(=O)c2ccccc2)c(Cl)s1

Cc1ccnc(SCC(=O)Nc2sc3c(c2C#N)CCCCC3)n1

MAR-TRE-1c920f6f-4

Cc1ccnc(SCC(=O)Nc2sc3c(c2C#N)CCCCC3)n1

Cc1ccnc(SCC(=O)Nc2sc3c(c2C#N)CCC(C)C3)n1

MAR-TRE-1c920f6f-5

Cc1ccnc(SCC(=O)Nc2sc3c(c2C#N)CCC(C)C3)n1

N#Cc1c(NC(=O)CSc2ncccn2)sc2c1CCCCC2

MAR-TRE-1c920f6f-7

N#Cc1c(NC(=O)CSc2ncccn2)sc2c1CCCCC2

N#Cc1c(NC(=O)CCn2cnnn2)sc2c1CCC2

MAR-TRE-1c920f6f-8

N#Cc1c(NC(=O)CCn2cnnn2)sc2c1CCC2

COC(=O)CC(=O)CSc1nc2c(cc1C#N)CCCCC2

MAR-TRE-1c920f6f-11

COC(=O)CC(=O)CSc1nc2c(cc1C#N)CCCCC2

Cc1cc(SCC(=O)Nc2sc3c(c2C#N)CCCC3)ncn1

MAR-TRE-1c920f6f-12

Cc1cc(SCC(=O)Nc2sc3c(c2C#N)CCCC3)ncn1

COC(=O)CSc1nc2c(cc1C#N)C(=O)CCC2

MAR-TRE-1c920f6f-13

COC(=O)CSc1nc2c(cc1C#N)C(=O)CCC2

N#Cc1cc2c(nc1SCC(=O)Nc1ccc(S(N)(=O)=O)cc1)CCC2

MAR-TRE-1c920f6f-19

N#Cc1cc2c(nc1SCC(=O)Nc1ccc(S(N)(=O)=O)cc1)CCC2

Cc1cc(C)c(C#N)c(SCC(=O)Nc2ccc(C(N)=O)cc2)n1

MAR-TRE-1c920f6f-20

Cc1cc(C)c(C#N)c(SCC(=O)Nc2ccc(C(N)=O)cc2)n1

N#Cc1c(NC(=O)CSc2nnc[nH]2)sc2c1CCCC2

MAR-TRE-1c920f6f-21

N#Cc1c(NC(=O)CSc2nnc[nH]2)sc2c1CCCC2

Cc1ccc(NC(=O)CSc2ncccc2C#N)cc1Cl

MAR-TRE-1c920f6f-26

Cc1ccc(NC(=O)CSc2ncccc2C#N)cc1Cl

N#Cc1ccc(CSc2nnc(-c3ccncc3)o2)cc1

MAR-TRE-1c920f6f-27

N#Cc1ccc(CSc2nnc(-c3ccncc3)o2)cc1

N#CCN(CC#N)S(=O)(=O)Cc1ccc(Cl)cc1

MAR-TRE-1c920f6f-28

N#CCN(CC#N)S(=O)(=O)Cc1ccc(Cl)cc1

Cc1cc(C)c(C#N)c(SCC(=O)c2ccc(O)c(O)c2)n1

MAR-TRE-1c920f6f-29

Cc1cc(C)c(C#N)c(SCC(=O)c2ccc(O)c(O)c2)n1

Cc1ccc(NC(=O)CSc2ncccc2C#N)cc1F

MAR-TRE-1c920f6f-30

Cc1ccc(NC(=O)CSc2ncccc2C#N)cc1F

N#Cc1c(NC(=O)CCn2cnnn2)sc2c1CCCC2

MAR-TRE-1c920f6f-32

N#Cc1c(NC(=O)CCn2cnnn2)sc2c1CCCC2

N#Cc1cccc(CSc2nnc(-c3ccncc3)o2)c1

MAR-TRE-1c920f6f-34

N#Cc1cccc(CSc2nnc(-c3ccncc3)o2)c1

Cn1nnnc1SCC(=O)Nc1sc2c(c1C#N)CCCCC2

MAR-TRE-1c920f6f-37

Cn1nnnc1SCC(=O)Nc1sc2c(c1C#N)CCCCC2

N#Cc1ccc(CSc2nnc(-c3ccncc3)[nH]2)cc1

MAR-TRE-1c920f6f-39

N#Cc1ccc(CSc2nnc(-c3ccncc3)[nH]2)cc1

Cc1nnc(SCC(=O)Nc2sc3c(c2C#N)CCCC3)s1

MAR-TRE-1c920f6f-41

Cc1nnc(SCC(=O)Nc2sc3c(c2C#N)CCCC3)s1

N#Cc1ccc(CSc2nnc(-c3ccco3)o2)cc1

MAR-TRE-1c920f6f-43

N#Cc1ccc(CSc2nnc(-c3ccco3)o2)cc1

N#Cc1cccnc1SCC(=O)Nc1cccc(Br)c1

MAR-TRE-1c920f6f-44

N#Cc1cccnc1SCC(=O)Nc1cccc(Br)c1

CSc1nsc(SCC(=O)Nc2sc3c(c2C#N)CCCC3)n1

MAR-TRE-1c920f6f-45

CSc1nsc(SCC(=O)Nc2sc3c(c2C#N)CCCC3)n1

N#Cc1c(NC(=O)CSc2ncccn2)sc2c1CCCC2

MAR-TRE-1c920f6f-46

N#Cc1c(NC(=O)CSc2ncccn2)sc2c1CCCC2

N#Cc1cccnc1SCC(=O)Nc1ccc(Br)cc1

MAR-TRE-1c920f6f-47

N#Cc1cccnc1SCC(=O)Nc1ccc(Br)cc1

N#Cc1cccnc1SCC(=O)Nc1ccc(Br)cc1F

MAR-TRE-1c920f6f-49

N#Cc1cccnc1SCC(=O)Nc1ccc(Br)cc1F

N#Cc1c(NC(=O)CSc2nc[nH]n2)sc2c1CCCCC2

MAR-TRE-1c920f6f-51

N#Cc1c(NC(=O)CSc2nc[nH]n2)sc2c1CCCCC2

Cc1cc(C)c(C#N)c(SCC(=O)c2cccs2)n1

MAR-TRE-1c920f6f-53

Cc1cc(C)c(C#N)c(SCC(=O)c2cccs2)n1

CC(C)OC(=O)CSc1nc2c(cc1C#N)CCCCC2

MAR-TRE-1c920f6f-56

CC(C)OC(=O)CSc1nc2c(cc1C#N)CCCCC2

N#Cc1c(NC(=O)CSc2nnc(N)s2)sc2c1CCCCC2

MAR-TRE-1c920f6f-57

N#Cc1c(NC(=O)CSc2nnc(N)s2)sc2c1CCCCC2

N#Cc1cc2c(nc1SCC(=O)Nc1nccs1)CCCCC2

MAR-TRE-1c920f6f-58

N#Cc1cc2c(nc1SCC(=O)Nc1nccs1)CCCCC2

N#Cc1c(NC(=O)CSc2nnc(N)s2)sc2c1CCCC2

MAR-TRE-1c920f6f-60

N#Cc1c(NC(=O)CSc2nnc(N)s2)sc2c1CCCC2

CCc1nc(SCc2nc3ccccc3[nH]2)c(C#N)cc1C

MAR-TRE-1c920f6f-61

CCc1nc(SCc2nc3ccccc3[nH]2)c(C#N)cc1C

N#Cc1ccc(NC(=O)CSc2nc3ccccc3[nH]2)cc1

MAR-TRE-1c920f6f-65

N#Cc1ccc(NC(=O)CSc2nc3ccccc3[nH]2)cc1

COc1cccc2c(C)cc3nnc(SCC#N)n3c12

MAR-TRE-1c920f6f-67

COc1cccc2c(C)cc3nnc(SCC#N)n3c12

CCOC(=O)c1c(NC(=O)CC#N)sc2c1CCCCC2

MAR-TRE-1c920f6f-69

CCOC(=O)c1c(NC(=O)CC#N)sc2c1CCCCC2

Cc1cc(C)c(C#N)c(SCc2nnnn2-c2ccccc2)n1

MAR-TRE-1c920f6f-70

Cc1cc(C)c(C#N)c(SCc2nnnn2-c2ccccc2)n1

Cc1cc(C)c(C#N)c(SCC(=O)OCc2ccccc2)n1

MAR-TRE-1c920f6f-81

Cc1cc(C)c(C#N)c(SCC(=O)OCc2ccccc2)n1

N#Cc1cccnc1SCC(=O)N1CCc2ccccc21

MAR-TRE-1c920f6f-82

N#Cc1cccnc1SCC(=O)N1CCc2ccccc21

COc1cc(CO)c(Br)cc1OCc1ccccc1C#N

MAR-TRE-1c920f6f-83

COc1cc(CO)c(Br)cc1OCc1ccccc1C#N

Cc1ccc2[nH]c(CSc3nc(C)ccc3C#N)nc2c1

MAR-TRE-1c920f6f-86

Cc1ccc2[nH]c(CSc3nc(C)ccc3C#N)nc2c1

CCOC(=O)C(C#N)C(=O)c1ccc(NC(=O)c2cccc(OC)c2)cc1

MAR-TRE-1c920f6f-90

CCOC(=O)C(C#N)C(=O)c1ccc(NC(=O)c2cccc(OC)c2)cc1

Cc1c(Cl)cccc1NC(=O)COc1ccc(C#N)cc1

MAR-TRE-1c920f6f-91

Cc1c(Cl)cccc1NC(=O)COc1ccc(C#N)cc1

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

MAR-TRE-1c920f6f-94

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

Cc1cc(C)c(C#N)c(SCC(=O)Nc2ccc(S(N)(=O)=O)cc2)n1

MAR-TRE-1c920f6f-95

Cc1cc(C)c(C#N)c(SCC(=O)Nc2ccc(S(N)(=O)=O)cc2)n1

CCc1nc(SCC(=O)OCc2ccccc2)c(C#N)cc1C

MAR-TRE-1c920f6f-96

CCc1nc(SCC(=O)OCc2ccccc2)c(C#N)cc1C

COc1ccc(NC(=O)CSCc2ccc(C#N)cc2)cc1

MAR-TRE-1c920f6f-97

COc1ccc(NC(=O)CSCc2ccc(C#N)cc2)cc1

CCOC(=O)C(C#N)C(=O)c1ccc(NC(=O)c2ccc(Br)cc2)cc1

MAR-TRE-1c920f6f-98

CCOC(=O)C(C#N)C(=O)c1ccc(NC(=O)c2ccc(Br)cc2)cc1

CC(=O)c1ccc(NC(=O)CSc2nc(C)cc(C)c2C#N)cc1

MAR-TRE-1c920f6f-100

CC(=O)c1ccc(NC(=O)CSc2nc(C)cc(C)c2C#N)cc1


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 4 of 5.

Other Notes:

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

Discussion: