Dual and selective lipid inhibitors of cyclooxygenases and lipoxygenase: a molecular docking study

作者：Gaddipati Rajyalakshmi S^*; Raikundalia Gitesh K; Mathai Michael L

来源：Medicinal Chemistry Research, 2014, 23(7): 3389-3402.

DOI：10.1007/s00044-014-0919-y

• COX-1
• COX-2
• LOX
• Glide docking
• ROC curve
• Molecular dynamics simulation

The side effects of non-steroidal anti-inflammatory drugs (NSAIDs) concern the public, the government, and pharmaceutical companies. NSAIDs act as inhibitors of cyclooxygenases which are the major cause of pain and inflammation in our body. However, the inhibition of cyclooxygenases could divert arachidonic acid metabolism toward the lipoxygenase pathway leading to other forms of inflammation and tissue damage. Hence a common inhibitor that could block the action of both cyclooxygenases and lipoxygenase is of interest in medicinal chemistry research. Further, the inhibition of both cyclooxygenases-1 and 2 would result in more side effects, since blocking the action of cyclooxygenase-1 would cause gastrointestinal disturbance. Therefore, there is a need to find an inhibitor that acts on cyclooxygenase-2 and lipoxygenase without disturbing the action of cyclooxygenase-1. A molecular docking study with eight lipid ligands was conducted to find the common and selective inhibitors of these three enzymes. Docking with extra precision mode and standard precision mode was performed to find the suitable docking method using the Glide software tool. Docking with extra precision mode yielded better results than with standard precision mode. The docking results are validated using a receiver operator characteristic curve. Further, molecular dynamic simulations were performed for the docked complexes of lowest binding energies. The confirmations obtained from molecular dynamic simulations are more stable and credible than the docked confirmations. Docosahexaenoic acid, eicosapentaenoic acid, 2-arachidonyl glycerol, and anandamide are identified as dual inhibitors of cyclooxygenases and lipoxygenase. alpha-Tocotrienols are shown to be selective inhibitors of cyclooxygenase-2 and lipoxygenase.

• 出版日期2014-7