Computational protocol: Discovery of Leukotriene A4 Hydrolase Inhibitors Using Metabolomics Biased Fragment Crystallography†

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Protocol publication

[…] The ligand docking into LTA4H was carried out with the Surflex interface implemented in Sybyl 7.2 (Tripos Inc., St. Louis, MO). The Surflex-Dock engine uses an empirical scoring function and a patented search engine to dock ligands into a protein’s binding site.() The PDB ID 3CHI file was converted to a mole2 file, and hydrogens were added. The B-values were replaced by the AMBER charges using Sybyl 7.2. The bound ligand of 3CHI was removed from the binding site. The Surflex-Dock protomol, a computational representation of the intended binding site, was generated using the probes CH4, −N−H, and −C=O. The protomol directed the placement of the ligand during the docking process. LTA4H inhibitors were drawn in ISIS Draw and converted to 3D structures with CONCORD of Sybyl 7.2 (Tripos Inc., St. Louis, MO). All of the inhibitors were properly typed with hydrogens, and a 3D structure data file was created for docking. Each ligand was then fragmented which reduced the conformational space to be explored. The fragments were then aligned to the protomol probes. All the fragments were scored,() and the highest scoring fragment was kept as the head fragment. The tail fragments were selected on the basis of the similar principle, and gradual attachment was carried out to build the docked ligand. The poses were refined, eliminating those with excessive penetration into the protein. Thirty poses for each of the ligand were generated and visualized in the active site based on their Surflex scores. The best fitting ligand poses were chosen for further comparative structural analysis. […]

Pipeline specifications

Software tools Surflex-Dock, AMBER
Application Protein interaction analysis
Organisms Dipturus trachyderma
Chemicals Niacinamide, Leukotriene A4