The human soluble
epoxide hydrolase (sEH) is a bifunctional
enzyme
that modulates the levels of regulatory epoxy lipids. The hydrolase
activity is carried out by a catalytic triad located at the center
of a wide L-shaped binding site, which contains two hydrophobic subpockets
at both sides. On the basis of these structural features, it can be
assumed that desolvation is a major factor in determining the maximal
achievable affinity that can be attained for this pocket. Accordingly,
hydrophobic descriptors may be better suited to the search of novel
hits targeting this enzyme. This study examines the suitability of
quantum mechanically derived hydrophobic descriptors in the discovery
of novel sEH inhibitors. To this end, three-dimensional quantitative
structure–activity relationship (3D-QSAR) pharmacophores were
generated by combining electrostatic and steric or alternatively hydrophobic
and hydrogen-bond parameters in conjunction with a tailored list of
76 known sEH inhibitors. The pharmacophore models were then validated
by using two external sets chosen (i) to rank the potency of four
distinct series of compounds and (ii) to discriminate actives from
decoys, using in both cases datasets taken from the literature. Finally,
a prospective study was performed including a virtual screening of
two chemical libraries to identify new potential hits, which were
subsequently experimentally tested for their inhibitory activity on
human, rat, and mouse sEH. The use of hydrophobic-based descriptors
led to the identification of six compounds as inhibitors of the human
enzyme with IC50< 20 nM, including two with IC50values of 0.4 and 0.7 nM. The results support the use of
hydrophobic descriptors as a valuable tool in the search of novel
scaffolds that encode a proper hydrophilic/hydrophobic distribution
complementary to the target’s binding site.