Submission Details
Molecule(s):
O=C(Nc1cncc2ccccc12)[C@@H]1CN(S(=O)(=O)CC2(Cl)CC2)Cc2ccc(Cl)cc21
O=C(Nc1cncc2cc(F)ccc12)[C@@H]1CN(S(=O)(=O)CC2(Cl)CC2)Cc2ccc(Cl)cc21
CC(C)(C#N)CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3cc(F)ccc23)C1
CN(C)CS(=O)(=O)N1Cc2ccc(Cl)cc2[C@H](C(=O)Nc2cncc3cc(F)ccc23)C1
Design Rationale:
There are four designs in this submission. Design 1 replaces the cyano substituent of MAT-POS-dc2604c4-1 with chloro with a view to improving potency (I would anticipate some deterioration in physicochemical characteristics). Normally a tertiary alkyl halide would be unacceptably electrophilic (SN1) but carbocations derived from cyclopropane are less stable than acyclic carbocations or those derived from larger rings and I’d expect a chlorocyclopropane to be acceptably non-electrophilic. Chlorine tends to be ‘sticky’ and, given the uncertainty in the binding mode, I think Design 1 would be worth a look. Designs 2 | 3 | 4 are, respectively, the 7-fluoro analogs of Design 1 | PET-UNK-af70882d-1 | PET-UNK-af70882d-3
Other Notes:
Protein-ligand complexes (P0157 A chain) were energy-minimized using Szybki (MMFF94S). The PDB file associated with this submission contains the following: [1] P0157 A chain protein structure [2] P0157 A chain crystallographic ligand (PET-UNK-29afea89-2) [3-6] Binding modes predicted for designs 1-4. I do not have a high degree of confidence in the modelled orientations of the groups linked to sulfonyl S.