Submission Details
Molecule(s):
NS(=O)(=O)CCCN(C(=O)Nc1cnccc1CNC(=O)NCCO)C1CCCCC1
NC(=O)CCCN(C(=O)Nc1cnccc1CNC(=O)NCCO)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:
The two compounds submitted here have elaborations extending from the linker ureido group designed to make bidentate hydrogen bonds with the sidechain of N142 as well as a hydroxy-ethyl methylurea substituent on the pyridyl ring to pick up extra contacts with the sidechain of E166 and main-chain oxygen/nitrogen atoms presented by the L167-G170 loop. Both compounds have low picomolar - nanomolar affinity prediction in SeeSAR, compound 1 (sulphonamide) better than compound 2 (amide). The SeeSAR models of compounds1 & 2 give CSMlig scores of 8.9 and 9.6 respectively so inverting the affinity order, but also suggesting picomolar - low nanomolar affinity.