title: Kinetics and docking studies of a COX-2 inhibitor isolated from Terminalia bellerica fruits.
abstract: Triphala is an Ayurvedic herbal formulation consisting of equal parts of three myrobalans: Terminalia chebula, Terminalia bellerica and Emblica officinalis. We recently reported that chebulagic acid (CA) isolated from Terminalia chebula is a potent COX-2/5-LOX dual inhibitor. In this study, compounds isolated from Terminalia bellerica were tested for inhibition against COX and 5-LOX. One of the fractionated compounds showed potent inhibition against COX enzymes with no inhibition against 5-LOX. It was identified as gallic acid (GA) by LC-MS, NMR and IR analyses. We report here the inhibitory effects of GA, with an IC(50) value of 74 nM against COX-2 and 1500 nM for COX-1, showing ≈20 fold preference towards COX-2. Further docking studies revealed that GA binds in the active site of COX-2 at the non-steroidal anti-inflammatory drug (NSAID) binding site. The carboxylate moiety of GA interacts with Arg120 and Glu524. Based on substrate dependent kinetics, GA was found to be a competitive inhibitor of both COX-1 and COX-2, with more affinity towards COX-2. Taken together, our studies indicate that GA is a selective inhibitor of COX-2. Being a small natural product with selective and reversible inhibition of COX-2, GA would form a lead molecule for developing potent anti-inflammatory drug candidates.
authors.affiliation: Department of Animal Sciences, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
authors.forename: Tamatam Chandramohan
authors.initials: TC
authors.lastname: Reddy
authors.forename: Polamarasetty
authors.initials: P
authors.lastname: Aparoy
authors.forename: Neela Kishore
authors.initials: NK
authors.lastname: Babu
authors.forename: Kotha Anil
authors.initials: KA
authors.lastname: Kumar
authors.forename: Suresh Kumar
authors.initials: SK
authors.lastname: Kalangi
authors.forename: Pallu
authors.initials: P
authors.lastname: Reddanna
mesh_terms: D000818:Animals; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005638:Fruit / Q000737:chemistry*; D005707:Gallic Acid / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D015394:Molecular Structure; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D029766:Terminalia / Q000737:chemistry*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D005707:Gallic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D008249:Protein-Lysine 6-Oxidase