Submission Details
Molecule(s):
C=CC(=O)Nc1cc(N(C)C)c(NCCN(C)C)cc1Nc1nccc(C(N)=O)n1
C=CC(=O)Nc1cc(N(CC)CC)c(NCCC)cc1Nc1nccc(C(N)=O)n1
C=CC(=O)Nc1cc(N(CC)CC)c(NCCN(C)C)cc1Nc1nccc(C(N)=O)n1
Design Rationale:
Acrylamide, loosely based on the Cys-modifying drug osimertinib. The compound was docked with the vinyl group in close proximity to Cys145 using the structure generated with the x0072 fragment (pdb 5R7Y). Docking and partial minimization was performed with Nanome (virtual reality). Two clefts are occupied by the dimethyl/diethylamine and the propylamine/ethylenediamine moieties. There are multiple H bonds to Asn142 (involving the carbonyl oxygen of the amido group on the pyrimidine ring, the amine between the pyrimidine and phenyl rings, and the nitrogen of the acrylamide moiety). There is also an H-bond between one of the ethylenediamine nitrogens (protonated) and the backbone carbonyl oxygen of Glu166.