Abstract
Human arginase I (hARGI) is an important enzyme involved in the urea cycle; its overexpression has been associated to cardiovascular and cerebrovascular diseases. In the last years, several congeneric sets of hARGI inhibitors have been reported with possible beneficial roles for the cardiovascular system. At the same time, crystallographic data have been reported including hARGI–inhibitor complexes, which can be considered for the design of novel inhibitors. In this work, the structure–activity relationship (SAR) of Cα substituted 2(S)-amino-6-boronohexanoic acid (ABH) derivatives as hARGI inhibitors was studied by using a three-dimensional quantitative structure–activity relationships (3D-QSAR) method. The predictivity of the obtained 3D-QSAR model was demonstrated by using internal and external validation experiments. The best model revealed that the differential hARGI inhibitory activities of the ABH derivatives can be described by using steric and electrostatic fields; the local effects of these fields in the activity are presented. In addition, binding modes of the above-mentioned compounds inside the hARGI binding site were obtained by using molecular docking. It was found that ABH derivatives adopted the same orientation reported for ABH within the hARGI active site, with the substituents at Cα exposed to the solvent with interactions with residues at the entrance of the binding site. The hARGI residues involved in chemical interactions with inhibitors were identified by using an interaction fingerprints (IFPs) analysis.
Highlights
Human arginase is the essential enzyme in the last step of the urea cycle of the human body, catalyzing the hydrolysis of L-arginine into L-ornithine and urea
Pudlo et al [4] indicated that high concentrations of human arginase I (hARGI) in the liver are enough for maintaining the function of this organ, while arginases are inhibited in other tissues
The interaction fingerprints (IFPs) analysis applied to the 18 hARGI–inhibitor complexes reported in Protein Data Bank (PDB) revealed that 16 hARGI residues had contacts with inhibitors (Figure 6B)
Summary
Human arginase (hARG) is the essential enzyme in the last step of the urea cycle of the human body, catalyzing the hydrolysis of L-arginine into L-ornithine and urea. EEsx.perimental and predicted pIC50 values 3 of 20. S−c54o.r35i76n53g pICE50−−nv77ea..r56lgu15ie94ess (k−ca4l.5/m63ol) Scorin3gof E−−−n7575e...r55636g1257i9745es pIC(k50cvaall/umeos l). −6.206 predicted pIC50 values using Model SE aTnadbldeo1c.kiSntrguGctluidrees socfoAriBnTHgaebannleearlo1gg.ysCvaoasnluhtAe. sR.GI inhibitors. The test set predicted pIC50 values are listed, and the correlations between the predicIntti.oJ.nMsoal.nSdci. This analysis demons7troaf t2e0d the abilities of Model SE for predicting novel compounds. A unique yellow contour (Y1 in Figure 3A) is located in front of CH2 of the benzyl group of compound p3_11c, which indicates that bulky groups in this region are not required for increasing hARGI inhibitory activity. Compounds p2_1j, p2_1k, and p2_il, which are among the most active compounds of the series p2_x, contain HB donor NH groups in this region
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