Molecular docking studies of human COX-2 with selective terpenoids inhibitors

Abstract

The Cyclooxygenase isozymes COX-1 and COX-2 are rate-limiting enzymes involved in the conversion of arachidonic acid into inflammatory prostaglandins. The chronic inflammation predispose to carcinogenesis. The COX-2 is highly inducible during the inflammation. COX-1 inhibitors had side effects as gastric ulceration. However COX-2 selective inhibitors are believed to have the same anti-inflammatory, anti-pyretic and analgesic activities as that of nonselective inhibitor NSAIDs with little or none of the gastrointestinal side effect, but still have cardiovascular side effects. Moreover the rofecoxib is a better selective compound with more than 50-fold COX-2. To find alternative solution studies suggested that natural inhibitors can help to find new drugs and terpenoids are a good candidate to be analyzing for their anti-inflammatory effect. In this paper selective terpenoids namely ursolic acid, bartsioside, aucubin, 8-acetylharpagide, harpagoside, hinokinin, betulinic acid, roburic acid, fomitopinic acid A and fomitoside E was analyzed through a molecular docking study and compared to rofecoxib and their drug like proprieties on the basis of ADMET and Lipinski rules of five. In silico ADMET study was performed to assess drug likeness and toxicity profiles of selected molecules. The experimental analysis of selected terpenoids and rofecoxib exhibited good COX-2 inhibitory activity and selectivity. The prediction of the binding modes suggested interactions with Ile517, Phe518 and Gln192 for the followings iridoids, harpagoside, 8-acetylharpagoside, aucubin and bartioside that are very similar to rofecoxib in the 5KIR COX-2 structure. In addition the described docking showed bartioside lower binding energy (−10,53 kcal/mol) and interactions in the active site with key residues His90 - Phe518 - Ile517 - Ser353. Moreover bartioside was found to be best as far as inhibition of COX-2 is according to the correlation between our in silico results, the experiment data, lipinski’s rule and ADMET predictions. This study opens up a new platform for the development of bartioside as a based on natural drugs for treating.