Submission Details
Molecule(s):
Cc1ccncc1NC(=O)N(CCCS(=O)(=O)NCCC(N)=O)C1CCCCC1
Cc1ccncc1NC(=O)N(CCCS(=O)(=O)NCc1ccn[nH]1)C1CCCCC1
Cc1ccncc1NC(=O)N(CCCS(=O)(=O)NCCc1ccn[nH]1)C1CCCCC1
Design Rationale:
Protein model x967: Sidechains of M49 and M165 have rotated to create a more open pocket. Sidechain of N142 also flipped providing different H-bond opportunities. Fragment expansion: Ligands based on extension of pyridyl fragment of x107 into pocket between M49 and M165 using position of benzyl group of x72 as an initial guide. Fragments found by searching REAL database, various sets aligned in Pharmit using x967 receptor model and x107 and x72 ligands to define pharmacophore features. Top set screened through SeeSAR and SeeSAR models also checked with CSM-lig. Cyclohexane linked to x107 pyridyl moiety by ureido group makes an excellent core scaffold. Elaborations from the pyridyl ring, ureido nitrogens and cyclohexyl ring system examined.
Other Notes:
1st above compound has pico-nanomolar affinity prediction in SeeSAR and a score of 9.3 in CSM-lig. 2nd compound has pico-nanomolar affinity prediction in SeeSAR and a score of 11.3 in CSM-lig. 3rd compound has nanomolar affinity in SeeSAR due to small close proximity clash in the ethyl pyrazole extension, but this looks resolvable with small movement of surrounding protein and the extra linker carbon allows bidentate interaction of the pyrazole nitrogens with adjacent T26 main-chain nitogen and T24 main-chain oxygen. CSMlig score 11.3 All 3 ligands are in the uploaded pdb, NC1-3 = compound 1-3. Datawarrior does not identify any nasty functional groups or known tumurogenic / mutagenic / reproductive affect / irritant motifs