Quantitative structure activity relationship and binding investigation of N-alkyl glycine amides as inhibitors of Leukotriene A4 hydrolase

Abstract

The leukotriene A4 hydrolase (LTA4H) is a bifunctional zinc enzyme that catalyzes the final (ratelimiting) step in the synthesis of leukotriene B4 (LTB4), which is involved in several diseases. Many pharmaceutical attempts to exploit the LTA4H/LTB4 pathway have been unsatisfactory, hence, the development of new inhibitory drugs is essential. This paper describes the generation of a quantitative structure-activity relationship (QSAR) model on a series of 50 N-alkyl glycine amides with experimentally defined IC 50 . In addition, the optimized molecular structures of the inhibitors were docked into the active site of the enzyme to identify the enzymeligand interactions and quantify the estimated free energy of binding (DG bind ). A simple four-descriptor QSAR model with high predictive capacity was obtained. The statistic parameters of the model are: regression coefficient (R test ) of 0.714 and a standard deviation (S test ) of 0.696. The predicted inhibitory activity of 85 new N-alkyl glycine amides compounds was obtained with this QSAR model and these compounds were docked into LTA4H. Ten of the compounds present predicted IC 50 values lower than 10 nM and binding poses and affinity values similar to the natural ligand (leukotriene A4), turning them into suitable candidates for experimental assays.

QM/MM Molecular Dynamics Investigations of the Substrate Binding of Leucotriene A4 Hydrolase: Implication for the Catalytic Mechanism

“…Recently, the inhibitor design for LTA4H has received much attention due to its dual function in anti- and pro-inflammatory roles. ,,− However, most of the inhibitors show no inhibition specificity against activities of both peptidase and epoxide hydrolase, except the recently reported ARM1, which was shown to bind in the hydrophobic pocket but leave the peptidase active site unoccupied. Although kinetic investigations and crystal structures have been reported for both aminopeptidase and epoxide hydrolase in some detail, some important issues are still not well understood.…”