Abstract

Objective: To clarify the molecular inhibition mechanism of harpagoside and harpagide with cyclooxygenase-2 (COX-2) as natural potent anti-inflammatory and anti-analgestic compounds derived from the Harpagophytum species and evaluate the drug-likeness and pharmacokinetic characteristics of both compounds. Methods: The X-ray crystal structure of the COX-2 enzyme and harpagoside and harpagide were retrieved and energetically minimized by SPDV viewer and ChemAxon softwares, respectively. Then, all nonpolar hydrogens were merged, and partial atomic charges were assigned using the Gasteiger-Marsili method. The binding sites and surfaces of enzymes were detected. In addition, docking studies were performed by AutoDock 4.2 using the Lamarckian genetic algorithm. Finally, the drug-likeness and molecular pharmacokinetic properties of the compounds were calculated. Results: Molecular docking showed that both harpagoside and harpagide interact with COX-2, and their binding energies were –9.13 and –5.53 kcal/mol, respectively. Furthermore, interactions were stabilized for harpagoside and harpagide within the active site of COX-2 by 7 and 10 hydrogen bonds, respectively. These results suggested that harpagoside and harpagide complied with most of Lipinski's rules. Bioactivity scores revealed that harpagoside was a moderate G protein-coupled receptor ligand, nuclear receptor ligand, protease inhibitor and enzyme inhibitor. Harpagide is a suitable enzyme inhibitor and moderate G protein-coupled receptor ligand, ion channel modulator, nuclear receptor ligand, and protease inhibitor. Conclusions: Results clearly revealed that harpagoside and harpagide act as potential highly selective COX-2 inhibitors. They are safe anti-inflammatory/analgesic compounds compared with classical non-steroidal anti-inflammatory drugs and could be considered as promising inflammatory inhibitors of a natural origin.

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