Journal:BMC:3
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The paper reports a novel scaffold containing isocytosine moiety that was discovered for xanthine oxidase inhibition by virtual screening and enzymatic assay. Several co-crystal structures of xanthine oxidase and xanthine dehydrogenase (which do not differ in conformation of active site) were studied to understand key interactions for enzyme inhibition. Docking of novel hits and inactive compounds was performed (to <scene name='Journal:BMC:3/Cv/3'>protein</scene> in PDB with ID [[1vdv]]) to understand the ligand-protein interactions and hence, for structure-based design of more potent molecules. The paper reports the directions for modification of the hit compound derived from these considerations, which are reported below. The mechanism of action of the novel hits are like <scene name='Journal:BMC:3/Cv/6'>piraxostat</scene> and <scene name='Journal:BMC:3/Cv/5'>febuxostat</scene> (“pure inhibitors”) and not like <scene name='Journal:BMC:3/Cv/8'>allopurinol</scene> & '''FYX-051''' (“substrate inhibitors”). | The paper reports a novel scaffold containing isocytosine moiety that was discovered for xanthine oxidase inhibition by virtual screening and enzymatic assay. Several co-crystal structures of xanthine oxidase and xanthine dehydrogenase (which do not differ in conformation of active site) were studied to understand key interactions for enzyme inhibition. Docking of novel hits and inactive compounds was performed (to <scene name='Journal:BMC:3/Cv/3'>protein</scene> in PDB with ID [[1vdv]]) to understand the ligand-protein interactions and hence, for structure-based design of more potent molecules. The paper reports the directions for modification of the hit compound derived from these considerations, which are reported below. The mechanism of action of the novel hits are like <scene name='Journal:BMC:3/Cv/6'>piraxostat</scene> and <scene name='Journal:BMC:3/Cv/5'>febuxostat</scene> (“pure inhibitors”) and not like <scene name='Journal:BMC:3/Cv/8'>allopurinol</scene> & '''FYX-051''' (“substrate inhibitors”). | ||
- | Functional aspects of xanthine oxidase''' | + | '''Functional aspects of xanthine oxidase''' |
Xanthine oxidoreductase (XOR), is an oxidoreductive enzyme that is synthesized as xanthine dehydrogenase (XDH) and can be converted reversibly or irreversibly to xanthine oxidase (XO) form. It catalyzes the <scene name='Journal:BMC:3/Cv/13'>transformation of physiological substrates</scene> such as <scene name='Journal:BMC:3/Cv/16'>hypoxanthine to xanthine</scene> and <scene name='Journal:BMC:3/Cv/17'>xanthine to uric acid</scene> which is excreted by kidneys.<ref name="Pauff">PMID:19109252</ref> The reaction occurs at the <scene name='Journal:BMC:3/Cv2/5'>cofactor molybdopterin (Mo-Pt)</scene> center from where the <scene name='Journal:BMC:3/Cv2/6'>electrons are transferred via two Fe2S2 clusters to FAD, which then passes them on to the second substrate NAD+</scene> in case of XDH (PDB code [[2w3s]])<ref name="Xan">PMID: 19109249</ref> or to molecular oxygen in XO leading to the formation of superoxide anion and H<sub>2</sub>O<sub>2</sub>. Excessive production and/or inadequate excretion of uric acid results in hyperuricemia and is associated with conditions like gout, cardiovascular mortality and metabolic syndrome including hyperinsulinemia and hypertriglyceridemia. Alleviating hyperuricemia, therefore, has therapeutic significance, and XO is a key target towards this end. | Xanthine oxidoreductase (XOR), is an oxidoreductive enzyme that is synthesized as xanthine dehydrogenase (XDH) and can be converted reversibly or irreversibly to xanthine oxidase (XO) form. It catalyzes the <scene name='Journal:BMC:3/Cv/13'>transformation of physiological substrates</scene> such as <scene name='Journal:BMC:3/Cv/16'>hypoxanthine to xanthine</scene> and <scene name='Journal:BMC:3/Cv/17'>xanthine to uric acid</scene> which is excreted by kidneys.<ref name="Pauff">PMID:19109252</ref> The reaction occurs at the <scene name='Journal:BMC:3/Cv2/5'>cofactor molybdopterin (Mo-Pt)</scene> center from where the <scene name='Journal:BMC:3/Cv2/6'>electrons are transferred via two Fe2S2 clusters to FAD, which then passes them on to the second substrate NAD+</scene> in case of XDH (PDB code [[2w3s]])<ref name="Xan">PMID: 19109249</ref> or to molecular oxygen in XO leading to the formation of superoxide anion and H<sub>2</sub>O<sub>2</sub>. Excessive production and/or inadequate excretion of uric acid results in hyperuricemia and is associated with conditions like gout, cardiovascular mortality and metabolic syndrome including hyperinsulinemia and hypertriglyceridemia. Alleviating hyperuricemia, therefore, has therapeutic significance, and XO is a key target towards this end. |
Revision as of 10:30, 27 March 2012
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- ↑ B-Rao C, Kulkarni-Almeida A, Katkar KV, Khanna S, Ghosh U, Keche A, Shah P, Srivastava A, Korde V, Nemmani KV, Deshmukh NJ, Dixit A, Brahma MK, Bahirat U, Doshi L, Sharma R, Sivaramakrishnan H. Identification of novel isocytosine derivatives as xanthine oxidase inhibitors from a set of virtual screening hits. Bioorg Med Chem. 2012 May 1;20(9):2930-9. Epub 2012 Mar 14. PMID:22483591 doi:10.1016/j.bmc.2012.03.019
- ↑ Pauff JM, Cao H, Hille R. Substrate Orientation and Catalysis at the Molybdenum Site in Xanthine Oxidase: CRYSTAL STRUCTURES IN COMPLEX WITH XANTHINE AND LUMAZINE. J Biol Chem. 2009 Mar 27;284(13):8760-7. Epub 2008 Dec 24. PMID:19109252 doi:10.1074/jbc.M804517200
- ↑ Dietzel U, Kuper J, Doebbler JA, Schulte A, Truglio JJ, Leimkuhler S, Kisker C. Mechanism of Substrate and Inhibitor Binding of Rhodobacter capsulatus Xanthine Dehydrogenase. J Biol Chem. 2009 Mar 27;284(13):8768-76. Epub 2008 Dec 24. PMID:19109249 doi:http://dx.doi.org/10.1074/jbc.M808114200
- ↑ Fukunari A, Okamoto K, Nishino T, Eger BT, Pai EF, Kamezawa M, Yamada I, Kato N. Y-700 [1-[3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid]: a potent xanthine oxidoreductase inhibitor with hepatic excretion. J Pharmacol Exp Ther. 2004 Nov;311(2):519-28. Epub 2004 Jun 9. PMID:15190124 doi:10.1124/jpet.104.070433
- ↑ 5.0 5.1 Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF, Nishino T. An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J Biol Chem. 2003 Jan 17;278(3):1848-55. Epub 2002 Nov 5. PMID:12421831 doi:10.1074/jbc.M208307200
- ↑ Truglio JJ, Theis K, Leimkuhler S, Rappa R, Rajagopalan KV, Kisker C. Crystal structures of the active and alloxanthine-inhibited forms of xanthine dehydrogenase from Rhodobacter capsulatus. Structure. 2002 Jan;10(1):115-25. PMID:11796116
- ↑ 7.0 7.1 Okamoto K, Matsumoto K, Hille R, Eger BT, Pai EF, Nishino T. The crystal structure of xanthine oxidoreductase during catalysis: implications for reaction mechanism and enzyme inhibition. Proc Natl Acad Sci U S A. 2004 May 25;101(21):7931-6. Epub 2004 May 17. PMID:15148401 doi:10.1073/pnas.0400973101
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