Molecular Docking-Based Screening of Phytohormone-Derived Compounds Against Soluble Epoxide Hydrolase and Cyclooxygenase-2: An In Silico Study With ADME-Based Pharmacokinetic Profiling

Abstract

Background: Chronic inflammation and metabolic disorders, including cardiovascular disease and type 2 diabetes mellitus, share a common pathophysiological basis in dysregulated lipid mediator signaling. Soluble epoxide hydrolase (sEH; EC 3.3.2.10) and cyclooxygenase-2 (COX-2) are validated pharmacological targets in these pathways. Current synthetic sEH inhibitors face challenges including metabolic instability and limited selectivity, motivating exploration of natural product-derived scaffolds. Phytohormones represent an underexplored ligand space for multi-target anti-inflammatory drug discovery. Objective: This study aimed to identify phytohormone-derived compounds with favorable predicted binding affinity at the sEH catalytic site (PDB: 3EBL) and COX-2 (PDB: 5F19), and to assess their oral drug-likeness through ADME profiling. Methods: Seven structurally diverse phytohormones were prepared using Open Babel v2.4.1 and docked against sEH (PDB: 3EBL) and COX-2 (PDB: 5F19) using AutoDock Vina v1.1.2. Grid boxes were centered on the co-crystallized ligand binding site. Docking protocol validity was confirmed by self-docking (RMSD < 2.0 Å). ADME properties and Lipinski drug-likeness were evaluated using SwissADME. Key Results: Abscisic acid (ABA) showed the most favorable predicted binding affinity at the sEH active site (ΔG = −6.4 kcal/mol), with predicted hydrogen-bond interactions at residues ASP213 and ARG210, consistent with known sEH pharmacophoric requirements. At COX-2, ABA also produced the lowest predicted energy (−5.6 kcal/mol). ABA, jasmonic acid, methyl jasmonate, and indole-3-acetic acid satisfied Lipinski’s Rule of Five, with ABA displaying high predicted gastrointestinal absorption (TPSA = 77.8 Ų) and no structural alerts. Conclusion: Abscisic acid is identified as a computationally prioritized lead for sEH inhibition with an acceptable in silico pharmacokinetic profile. Experimental validation through enzyme inhibition assays and biophysical binding studies is required before pharmacological conclusions can be drawn.

Keywords

Natural Science - Biology, Applied Science - Applied Biological Science

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