Reddy Tamatam Chandramohan, Aparoy Polamarasetty, Babu Neela Kishore, Kumar Kotha Anil, Kalangi Suresh Kumar, Reddanna Pallu
Department of Animal Sciences, School of Life Sciences, University of Hyderabad, Hyderabad 500046, India.
Protein Pept Lett. 2010 Oct;17(10):1251-7. doi: 10.2174/092986610792231537.
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.
三果木是一种阿育吠陀草药配方，由三种诃子（毗黎勒、毛诃子和余甘子）等量组成。我们最近报道，从毗黎勒中分离出的诃子鞣酸是一种有效的COX - 2/5 - LOX双重抑制剂。在本研究中，对从毛诃子中分离出的化合物进行了COX和5 - LOX抑制测试。其中一种分离出的化合物对COX酶有强效抑制作用，对5 - LOX无抑制作用。通过液相色谱 - 质谱联用（LC - MS）、核磁共振（NMR）和红外光谱（IR）分析，将其鉴定为没食子酸（GA）。我们在此报告GA的抑制作用，其对COX - 2的IC(50)值为74 nM，对COX - 1为1500 nM，对COX - 2的偏好性约为20倍。进一步的对接研究表明，GA在非甾体抗炎药（NSAID）结合位点结合于COX - 2的活性位点。GA的羧基部分与Arg120和Glu524相互作用。基于底物依赖性动力学，发现GA是COX - 1和COX - 2的竞争性抑制剂，对COX - 2的亲和力更高。综上所述，我们的研究表明GA是COX - 2的选择性抑制剂。作为一种对COX - 2具有选择性和可逆抑制作用的小型天然产物，GA将成为开发强效抗炎候选药物的先导分子。
