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1、 ITB J. Sci., Vol. 44 A, No. 1, 2012, 51-66 51In vitro and In Silico Studies on Curcumin andIts Analogues as Dual Inhibitors for cyclooxygenase-1(COX-1) and cyclooxygenase-2 (COX-2)Nunung Yuniarti , Perdana Adhi Nugroho , Aditya Asyhar , Sardjiman , 1 2 2 31 4Zullies Ikawati& Enade Perdana Istyaston
2、o1Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia2Curcumin Research Centre, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada,
3、Yogyakarta, Indonesia4Leiden/Amsterdam Center for Drug Research (LACDR), Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Exact Sciences, Vrije University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The NetherlandsEmail: nungki_fa97yahoo Abstract. Curcumin has been w
4、idely reported as an anti-inflammatory agent isolated from the plant Curcuma longa L. (turmeric). This anti-inflammatory activity was associated with the ability of this compound to inhibit the activity of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in arachidonic acid metabolism. Dua
5、l COX-1 and COX-2 inhibitors are preferred to be employed in the therapy of chronic inflammatory diseases compared to selective inhibitors, since it was reported that the use of selective inhibitors led to severe adverse side effect. In the present study, in vitro and in silico assays on curcuminand
6、 its analogues as dual inhibitors for both COX-1 and COX-2 were performed. The results provide theoretical contribution in understanding the ligand-protein interactions at the molecular level to develop new curcumin analogues which possess better anti-inflammatory activity as well as to avoid unsoli
7、cited side effects.Keywords: curcumin; cyclooxygenase-1; cyclooxygenase-2; in silico docking; in vitro inhibition assay; dual inhibitor.1IntroductionCurcumin (Figure 1; compound 1a and 1b), the yellow pigment isolated fromthe plant Curcuma longa L. (turmeric), has been reported to have anti-inflamma
8、tory activity, as well as antiviral, antioxidant and anti-infectiousactivities 1,2. Moreover, in several studies, curcumin caused suppression,retardation, or inversion of carcinogenesis 3-6. The ability of curcumin toinhibit prostaglandins (PGs) biosynthesis in the arachidonic acid cascade hasReceiv
9、ed March 5 , 2010, Revised November 3 , 2011, Accepted for publication November 21 , 2011.th rd stCopyright 2012 Published by LPPM ITB, ISSN: 1978-3043, DOI: 10.5614/itbj.sci.2012.44.1.5 52Nunung Yuniarti, et al.been suggested as an important factor for its anti-inflammatory activity and itsanticarc
10、inogenic action 2-7. Enzyme cyclooxygenases (COXs), which consistof at least two isoforms, i.e., cyclooxygenase-1 (COX-1) and cyclooxygenase-2(COX-2), catalyze the conversion of arachidonic acid to PGH2 in the first twosteps 3,7,8. The first isoform, COX-1, has been suggested as a constitutivelyexpr
11、essed enzyme, which is responsible for maintaining normal physiologicalfunction 3,8. On the other hand, the second isoform, COX-2 is inducible andthe expression is stimulated in the inflammation process 7-9. At the beginningof the discovery of COX-2, therefore, the selectivity towards COX-2 wasconsi
12、dered as beneficial 10. However, the withdrawal of Rofecoxib, aselective COX-2 inhibitor, due to its increased risk of cardiovascular events,raises an issue that the development of the dual inhibitor of the COX-1 andCOX-2 is of considerable interest 8. Even more, the COX-1 and COX-2 dualinhibitors a
13、re suggested to be more appropriate for treating chronicinflammation 11.Figure 1 Structures of curcumin (1) in the keto (1a) and the enol (1b) forms, 2,5-bis(4-hydroxy-3-methoxybenzilidene)-cyclopentanone (2), 1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one (3), and flurbiprofen (4).Curcumin inhibits the PGs biosynthesis by inhibiting the activity ofcyclooxygenases(COXs),bothcyclooxygenase-1(COX-1)andcyclooxygenase-2 (COX-2) 2-7. The anti-inflammatory activity of curcuminwas related to its ability in inhibiting CO
