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Screening and Biological Evaluation of Soluble Epoxide Hydrolase Inhibitors: Assessing the Role of Hydrophobicity in the Pharmacophore-Guided Search of Novel Hits
- Source :
- Journal of chemical information and modeling, vol 63, iss 10
- Publication Year :
- 2023
- Publisher :
- eScholarship, University of California, 2023.
-
Abstract
- 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 IC50 values 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.
- Subjects :
- Epoxide Hydrolases
Pharmacophore
General Chemical Engineering
Medicinal & Biomolecular Chemistry
Quantitative Structure-Activity Relationship
Computation Theory and Mathematics
General Chemistry
Library and Information Sciences
Computer Science Applications
Rats
Mice
Medicinal and Biomolecular Chemistry
Theoretical and Computational Chemistry
Animals
Humans
Prospective Studies
Enzyme Inhibitors
Hydrophobic and Hydrophilic Interactions
Biotechnology
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Journal of chemical information and modeling, vol 63, iss 10
- Accession number :
- edsair.doi.dedup.....fe23643e703c293bb48aa443aa019c0f