Computational protocol: Improvement of kynurenine aminotransferase-II inhibitors guided by mimicking sulfate esters

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Protocol publication

[…] A crystal structure of human KAT-II (PDB ID: 2R2N []) was downloaded from the Protein Data Bank. 2R2N is a high resolution human KAT-II structure (1.95 Å) with the ligand, kynurenine, already occupying the active site. The PLP cofactor was removed from the active site of the protein as there was evidence it competed with the ligands in the inhibition studies. Optimisation and minimisation of the protein was performed using the Impref utility in IMPACT (Schrodinger LLC) and the OPLS-2005 [] force field, and hydrogen atoms were also added and water molecules not involved in the reaction were removed, using the protein preparation wizard in Maestro version 10.4.017 (Schrodinger LLC). The active site was determined by the location of kynurenine in the crystal structure. The ligands were prepared using LigPrep [], using the OPLS-2005 force field, and were docked using Glide [] with XP docking []. Both enantiomers of NS-1502 and JN-03 were docked, with the best scoring pose represented in the figures. […]

Pipeline specifications

Software tools Protein Preparation Wizard, LigPrep, Glide
Applications Drug design, Protein interaction analysis
Organisms Homo sapiens
Chemicals Estrogens, Kynurenic Acid, Kynurenine, Pyridoxal Phosphate