Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods

Background: Inflammation is a critical component of many disease progressions, such as malignancy, cardiovascular and rheumatic diseases. The inhibition of inflammatory mediators synthesis by modulation of cyclooxygenase (COX) and lipoxygenase (LOX) pathways provides challenging strategy for development of more effective drugs. Objective: The aim of this study was to design dual COX-2 and 5-LOX inhibitors with iron-chelating properties using a combination of ligand-based (three-dimensional quantitative structure-activity relationship (3D-QSAR)) and structure-based (molecular docking) methods. Methods: The 3D-QSAR analysis was applied on a literature dataset consisting of 28 dual COX-2 and 5-LOX inhibitors in Pentacle software. The quality of developed COX-2 and 5-LOX 3D-QSAR models were evaluated by internal and external validation methods. The molecular docking analysis was performed in GOLD software, while selected ADMET properties were predicted in ADMET predictor software. Results: According to the molecular docking studies, the class of sulfohydroxamic acid analogues, previously designed by 3D-QSAR, were clustered as potential dual COX-2 and 5-LOX inhibitors with iron-chelating properties. Based on the 3D-QSAR and molecular docking, 1j, 1g and 1l were selected as the most promising dual COX-2 and 5-LOX inhibitors. According to the in silico ADMET predictions, all compounds had ADMET_Risk score less than 7 and CYP_Risk score lower than 2.5. Designed compounds were not estimated as hERG inhibitors and 1j had improved intrinsic solubility (8.704) in comparison to the dataset compounds (0.411-7.946). Conclusion: By combining 3D-QSAR and molecular docking, three compounds (1j, 1g and 1l) were selected as the most promising designed dual COX-2 and 5-LOX inhibitors, for which good activity, as well as favourable ADMET properties and toxicity, are expected.