Submission Details
Molecule(s):
Cc1cccc(CO)c1NC(=O)NC(Cc1ccc(O)cc1)C(=O)N(CCCC(N)=O)CCNS(N)(=O)=O
NC(=O)CCCN(CCNS(N)(=O)=O)C(=O)C(Cc1ccc(O)cc1)NC(=O)Nc1c(F)cc(F)cc1F
NC(=O)CCCN(CCNS(N)(=O)=O)C(=O)C(Cc1ccc(O)cc1)NC(=O)Nc1ncc[nH]1
Design Rationale:
Fragment 72 is small but has some good contacts - switched CO1 from carbon to nitrogen for better solubility and enhanced H-bond possibilities. Fragment 967 has good shape complementarity, and the phenol has induced a sidechain flip in N142 creating parallel surface and nicely burying the phenol aromatic group. Phenol oxygen pincered between His163 and main-chain oxygen of Phe140 with 2 H-bonds - looks nice... Fragment 967 also well positioned for extension into cleft between Pro168 and E189, which region is largely unexploited in the initial fragment set. Terminal carbon in this direction ~3.3A from main-chain oxygen of E166, obvious potential enhancement by shift from amide to ureido with further extension into the P168/E189 cleft. propyl bromide group has hydrophobic contacts but there are several H-bonding possibilities close to the Br so swapped for an amide
Other Notes:
Converted X967 compound to ureido and removed propyl-bromide from the other end then searched Chemspace REAL database for fragments so that any suggested ligands identified would be chemically reasonable. ~1000 fragments downloaded from Chemspace and used for several different chemophore pattern alignments using Pharmit server. Higher value given to low RMSD shift than to calculated score, top 10 hits then extended with the propyl-amide group and linked to sulphonamide version of fragment 72. linked compounds assessed in Pharmit, best aligned models downloaded and combined with x967 pdb Best molecule pdb uploaded, scores -8.1 Pharmit, 8.7 CSM-lig