Submission Details
Molecule(s):
Cc1cc(NC(=O)CSc2nc3c(cc2C#N)CCCCC3)no1
N#CCSc1nc(S(=O)(=O)c2ccccc2)c(Cl)s1
N#Cc1cccnc1SCC(=O)Nc1ccccc1O
Cc1ccnc(SCC(=O)Nc2sc3c(c2C#N)CCCCC3)n1
Cc1ccnc(SCC(=O)Nc2sc3c(c2C#N)CCC(C)C3)n1
N#Cc1ccccc1OCCOCCN1CCCCC1
N#Cc1c(NC(=O)CSc2ncccn2)sc2c1CCCCC2
N#Cc1c(NC(=O)CCn2cnnn2)sc2c1CCC2
N#CCCN(CCC#N)c1nc2c(s1)CCCC2
CC1CCN(C(=O)CSc2ncccc2C#N)CC1
COC(=O)CC(=O)CSc1nc2c(cc1C#N)CCCCC2
Cc1cc(SCC(=O)Nc2sc3c(c2C#N)CCCC3)ncn1
COC(=O)CSc1nc2c(cc1C#N)C(=O)CCC2
COCc1cc(C)nc(SCc2ccccc2)c1C#N
CCOC(=O)CSc1nc2c(cc1C#N)CCCCC2
N#Cc1cc2c(nc1SCC(N)=O)CCCC2=O
CCOC(=O)CSc1nc2c(cc1C#N)CCCC2
Cc1nc(SCC#N)c2c3c(sc2n1)CCC3
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
N#Cc1c(NC(=O)CSc2nnc[nH]2)sc2c1CCCC2
Cn1cnnc1SCc1ccc(C#N)cc1Cl
N#CCn1c(=O)oc2ccccc21
Cc1ccc(Nc2nc(N)nc(CC#N)n2)cc1
CC(=O)CSc1nc2c(cc1C#N)CCCC2
Cc1ccc(NC(=O)CSc2ncccc2C#N)cc1Cl
N#Cc1ccc(CSc2nnc(-c3ccncc3)o2)cc1
N#CCN(CC#N)S(=O)(=O)Cc1ccc(Cl)cc1
Cc1cc(C)c(C#N)c(SCC(=O)c2ccc(O)c(O)c2)n1
Cc1ccc(NC(=O)CSc2ncccc2C#N)cc1F
Cc1cc(O)nc(SCc2cccc(C#N)c2)n1
N#Cc1c(NC(=O)CCn2cnnn2)sc2c1CCCC2
Cc1sc2nc(SCC#N)[nH]c(=O)c2c1C
N#Cc1cccc(CSc2nnc(-c3ccncc3)o2)c1
Cc1sc2ncn(CCC#N)c(=O)c2c1C
COc1cccc2c(C)cc(SCC#N)nc12
Cn1nnnc1SCC(=O)Nc1sc2c(c1C#N)CCCCC2
N#Cc1cc2c(nc1SCC(N)=O)CCC2
N#Cc1ccc(CSc2nnc(-c3ccncc3)[nH]2)cc1
Cc1nc(SCC#N)c2c(C)c(C)sc2n1
Cc1nnc(SCC(=O)Nc2sc3c(c2C#N)CCCC3)s1
N#Cc1cccnc1SCC(=O)Nc1ccccc1
N#Cc1ccc(CSc2nnc(-c3ccco3)o2)cc1
N#Cc1cccnc1SCC(=O)Nc1cccc(Br)c1
CSc1nsc(SCC(=O)Nc2sc3c(c2C#N)CCCC3)n1
N#Cc1c(NC(=O)CSc2ncccn2)sc2c1CCCC2
N#Cc1cccnc1SCC(=O)Nc1ccc(Br)cc1
N#CCN1C(=O)c2ccccc2S1(=O)=O
N#Cc1cccnc1SCC(=O)Nc1ccc(Br)cc1F
Cc1cc(=O)oc2cc(OCCC#N)ccc12
N#Cc1c(NC(=O)CSc2nc[nH]n2)sc2c1CCCCC2
Cc1ccc2[nH]c(SCC#N)nc2c1
Cc1cc(C)c(C#N)c(SCC(=O)c2cccs2)n1
CCc1cc2c(SCC#N)ncnc2s1
N#CCCSCc1ccc(C(=O)O)o1
CC(C)OC(=O)CSc1nc2c(cc1C#N)CCCCC2
N#Cc1c(NC(=O)CSc2nnc(N)s2)sc2c1CCCCC2
N#Cc1cc2c(nc1SCC(=O)Nc1nccs1)CCCCC2
COc1ccc(CCC(=O)NCC#N)cc1
N#Cc1c(NC(=O)CSc2nnc(N)s2)sc2c1CCCC2
CCc1nc(SCc2nc3ccccc3[nH]2)c(C#N)cc1C
N#CCCCn1cnc2sc3c(c2c1=O)CCCC3
Cc1cc2c(SCC#N)ncnc2s1
N#CC1C=CC(c2cccnc2)=NC1=O
N#Cc1ccc(NC(=O)CSc2nc3ccccc3[nH]2)cc1
Cc1nc(SCC#N)c2c3c(sc2n1)CCCC3
COc1cccc2c(C)cc3nnc(SCC#N)n3c12
CCOC(=O)COc1nc2c(cc1C#N)CCC2
CCOC(=O)c1c(NC(=O)CC#N)sc2c1CCCCC2
Cc1cc(C)c(C#N)c(SCc2nnnn2-c2ccccc2)n1
N#CCNS(=O)(=O)c1ccc(Cl)cc1
N#CCCS(=O)(=O)c1ccc(Cl)cc1
N#CCCn1nc(-c2ccccc2)cc1O
N#Cc1cccnc1SCC(=O)Nc1ccccc1F
N#Cc1ccc(NC(=O)CSc2ccccn2)cc1
CC1CCN(CCOCCOc2ccccc2C#N)CC1
N#CCc1nc(-c2cc3ccccc3oc2=O)cs1
CNc1oc(COc2ccc(C)cc2)nc1C#N
Cc1ccc(-c2nn(CCC#N)cc2CO)cc1
N#CCCS(=O)(=O)c1ccc(Br)cc1
Cc1cc(C)c(C#N)c(SCC(=O)OCc2ccccc2)n1
N#Cc1cccnc1SCC(=O)N1CCc2ccccc21
COc1cc(CO)c(Br)cc1OCc1ccccc1C#N
COCCNc1oc(-c2ccccc2C)nc1C#N
CSc1nc2c(cc1C#N)C(=O)CCC2
Cc1ccc2[nH]c(CSc3nc(C)ccc3C#N)nc2c1
COCCNc1oc(-c2cccc(C)c2)nc1C#N
N#CCc1nnc(-c2cccc(Cl)c2)[nH]1
N#CCC(=O)c1ccc(N)cc1
CCOC(=O)C(C#N)C(=O)c1ccc(NC(=O)c2cccc(OC)c2)cc1
Cc1c(Cl)cccc1NC(=O)COc1ccc(C#N)cc1
Cc1cccc2c(=O)[nH]c(CC#N)nc12
COc1cc(CO)ccc1OCc1ccccc1C#N
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
CCc1nc(SCC(=O)OCc2ccccc2)c(C#N)cc1C
COc1ccc(NC(=O)CSCc2ccc(C#N)cc2)cc1
CCOC(=O)C(C#N)C(=O)c1ccc(NC(=O)c2ccc(Br)cc2)cc1
N#CCSc1nc2ccccc2s1
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.