Submission Details
Molecule(s):
CC(=O)C=CC1(Cc2ccccc2)COC(Cn2cc3c(n2)CC(NC(=N)N)C3c2nc(Cc3ccccc3)co2)=N1
Design Rationale:
We had previously submitted a peptide ligand with sequence GFRGFS (submission # ABH-HOE-1cb). We converted it to a peptidomimetic molecule with a Michael acceptor for covalent bonding to Cys145 and docked it onto 6y2e PDB using rosetta ligand docking. The approximate ligand docking protocol is as follows, 1. First we used SiteHound to identify posssible ligand binding sites in 6y2e using a Methyl probe. Three binding sites were found but only the active site showed the highest score qualifying for the subsequent docking run. 2. The ligand was placed close to 6y2e at the XYZ coordinates obtained for high scoring solution from SiteHound. 10,000 docking poses were generated by restricting the ligand to a box of 10 Å radius and perturbing (rotation + translation) the ligand 5 Å. Rosetta calculated the interface_delta score which is approximate measure of the interaction between the ligand and the protein. Top 10 solution sorted using interface_delta score were manually inspected in pymol. All 10 solutions docked the ligand in the active site. Key Features of the docked pose are: - The peptidomimetic molecule contains two phenylalanines and one arginine. - The Michael acceptor is placed close to C145 for covalent bond formation - The N-term Phe occupies hydrophobic pocket formed by residues H41, M49, F140, H163 - The C-term Phe occupies hydrophobic pocket formed by residues M165, L167, F185 and V186 - Arg forms a salt-bridge to E166 and another polar contact to the backbone carbonyls of residues L167 and P168. The ligand buries a total surface area of ~ 500 Å^2. Please see discussions for some pictures of the docked structure and docking evaluation.