Submission Details
Molecule(s):
N#CN(C(=O)[C@@H]1CN(S(=O)(=O)CC2(C#N)CC2)C(=O)c2ccc(Cl)cc21)c1cncc2ccccc12
COC1(CS(=O)(=O)N2C[C@@H](C(=O)N(C#N)c3cncc4ccccc34)c3cc(Cl)ccc3C2=O)CC1
N#CN(C(=O)[C@@H]1CN(S(=O)(=O)CC2(C#N)CC2)Cc2ccc(Cl)cc21)c1cncc2ccccc12
N#CN(C(=O)C1CN(S(=O)(=O)CC2(C#N)CC2)C(=O)c2ccc(Cl)cc21)c1cncc2ccccc12
COC1(CS(=O)(=O)N2CC(C(=O)N(C#N)c3cncc4ccccc34)c3cc(Cl)ccc3C2=O)CC1
N#CN(C(=O)C1CN(S(=O)(=O)CC2(C#N)CC2)Cc2ccc(Cl)cc21)c1cncc2ccccc12
Design Rationale:
The three designs in this submission place a cyano substituent on the amide nitrogen for three THIQ/DHIQ sulfonamides. This was originally suggested as a means to form a covalent bond reversibly between ligand and catalytic cysteine and I would not expect it to ‘flip’ the trans/cis conformational preference of the amide in the same way that methylation does. However, the cyano substituent would also address potential ADMET issues (amide hydrolysis in vivo; active efflux linked to amide NH) even if the covalent bond did not form and I’ll link some more detailed discussion in a comment on the submission. I think that the cyano substituent could be put on using cyanogen bromide. The racemates for the three designs have also been included in the submission.
Other Notes:
Protein-ligand complexes (P1788 A chain) were energy-minimized using Szybki (MMFF94S) fixing the coordinates of the amide nitrogen and oxygen. The PDB file associated with this submission contains the following: [1] P1788 A chain protein structure [2] P1788 A chain crystallographic ligand (MAT-POS-dc2604c4-1) [3-5] Non-covalent binding modes predicted for Designs 1-3.