Submission Details
Molecule(s):
O=C(Nc1ccncn1)Nc1sc2cc(CCc3ncc[nH]3)[nH]c2c1CC1CCC(O)CC1
O=C(Nc1ccncn1)Nc1cc2[nH]cc(CCc3ncc[nH]3)c2s1
O=C(Nc1ccncn1)Nc1sc2cc[nH]c2c1CC1CCC(O)CC1
OC1CCC(Cc2csc3c(CCc4ncc[nH]4)c[nH]c23)CC1
Design Rationale:
Inspected the binding of all non-covalent fragments and identified three sub-pockets of the active site. Picked the three fragments that seemed to fit best and suggest an overlapping bicycle in the centre, where I decided to include a thiophene as this S - SH appeared to possibly be an important interaction with Cys145. These were fragments X0387, X0104, X0434. X072 and X195 were also shortlisted. Some tweaks were made due to the pharmacophore, e.g. the pyrimidine and the imidazole were added. I removed a nitrogen from the non-aromatic ring to avoid incorporating a charge but this could be added back in. Alternative ideas: Central bicycle could be broken up to expose S-H for disulfide bridge formation with Cys145. The three fragments together make quite a large molecule so I have included all combinations of two fragments in order to hit two of the three pockets. The urea could also be changed for an amide if that would be preferable.