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 (rate-limiting) 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 IC50. In addition, the optimized molecular structures of the inhibitors were docked into the active site of the enzyme to identify the enzyme-ligand interactions and quantify the estimated free energy of binding (ΔGbind). A simple four-descriptor QSAR model with high predictive capacity was obtained. The statistic parameters of the model are: regression coefficient (Rtest) of 0.714 and a standard deviation (Stest) 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 IC50 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.