Submission Details
Molecule(s):
C#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3[C@H](C(=O)Nc3cncc4ccccc34)C2)CC1
C#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3[C@@]3(CCN(c4cncc5ccccc45)C3=O)C2)CC1
O=C1N(c2cncc3ccccc23)CC[C@]12CN(S(=O)(=O)CC1(Cl)CC1)Cc1ccc(Cl)cc12
C#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3[C@@]3(CC(=O)N(c4cncc5ccccc45)C3=O)C2)CC1
O=C1C[C@]2(CN(S(=O)(=O)CC3(Cl)CC3)Cc3ccc(Cl)cc32)C(=O)N1c1cncc2ccccc12
C=C1C(=O)[C@]2(CN(S(=O)(=O)CC3(C#N)CC3)Cc3ccc(Cl)cc32)C(=O)N1c1cncc2ccccc12
C=C1C(=O)[C@]2(CN(CC(=O)NC)Cc3ccc(Cl)cc32)C(=O)N1c1cncc2ccccc12
C#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3C(C(=O)Nc3cncc4ccccc34)C2)CC1
C#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3C3(CCN(c4cncc5ccccc45)C3=O)C2)CC1
O=C1N(c2cncc3ccccc23)CCC12CN(S(=O)(=O)CC1(Cl)CC1)Cc1ccc(Cl)cc12
C#CC1(CS(=O)(=O)N2Cc3ccc(Cl)cc3C3(CC(=O)N(c4cncc5ccccc45)C3=O)C2)CC1
O=C1CC2(CN(S(=O)(=O)CC3(Cl)CC3)Cc3ccc(Cl)cc32)C(=O)N1c1cncc2ccccc12
C=C1C(=O)C2(CN(S(=O)(=O)CC3(C#N)CC3)Cc3ccc(Cl)cc32)C(=O)N1c1cncc2ccccc12
C=C1C(=O)C2(CN(CC(=O)NC)Cc3ccc(Cl)cc32)C(=O)N1c1cncc2ccccc12
Design Rationale:
The cyano hydrogen bond acceptor of MAT-POS-dc2604c4-1 appears to be making contact with non-polar molecular surface in the P1788 crystal structure. Designs 1-5 aim to extract additional affinity from binding site by replacing cyano with ethynyl or chloro which are less polar. I see the chloro as being more resistant than ethynyl to metabolism. I’d expect these chlorocyclopropanes to be much less electrophilic than a typical tertiary alkyl chloride and chloro tends to be ‘sticky’. Designs 6 and 7 target the catalytic cysteine by introducing an exocyclic carbon-carbon bond next to the ketone in EDJ-MED-a12e3a20-1 and EDJ-MED-a12e3a20-2 (I’m assuming that the presence of the ketone will facilitate synthesis). The racemates for all designs have been included in this submission.
Other Notes:
Protein-ligand complexes (P1788 A chain) were energy-minimized using Szybki (MMFF94S). 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) [3-7] Binding modes predicted for Designs 1-5 [8-9] Non-covalent binding modes predicted for Designs 6-7.