Molecular docking and binding study of harpagoside and harpagide as novel anti-inflammatory and anti-analgesic compound from Harpagophytum procumbens based on their interactions with COX-2 enzyme

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.