CONSTRUCTION OF IN SILICO STRUCTURE-BASED SCREENING TOOLS TO STUDY THE OXIDATIVE METABOLITES FORMATION OF CURCUMIN BY HUMAN CYTOCHROME 450 3A4

Dewi Setyaningsih, Muhammad Radifar, Yosi Bayu Murti, Enade Perdana Istyastono

Abstract


Cytochrome P450 3A4 (CYP3A4) is a phase 1 metabolism enzyme which is responsible for the metabolism of about 3040% drug in the market. This CYP3A4 is the most abundant CYP450 expressed in human body and also the one who is responsible for the biotransformation of most drugs. The competitive inhibition of curcumin (a yellow bioactive pigment discovered in Curcuma sp.) towards human CYP3A4 indicates that curcumin can be a substrate for the enzyme. In this study, in silico approaches employing molecular docking and interaction fingerprinting were used to predict the binding mode and the site of metabolism (SOM) of curcumin. Together with the SOMs retrieved previously and the list of possible reactions catalyzed by CYP3A4, the docking and fingerprinting results indicate that the most probable metabolite of curcumin metabolism by human CYP3A4 is an oxidative metabolite 1-(3,4-dihydroxyphenyl)-5hydroxy-7-(4-hydroxy-3-methoxy-phenyl)hepta-1,4,6-trien-3one.


Key words: site of metabolism (SOM), curcumin, biotransformation, in silico, molecular docking, protein-ligand interaction fingerprinting


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References


Anand P., Kunnumakkara AB., Newman RA., and Aggarwal, B.B., 2007, Bioavailability of curcumin: Problems and promises, Mol. Pharmaceutics, 4, 807-818.

Appiah-Opong R., Commandeur JNM., Axson C., and Vermeulen, NPE., 2008, Interactions between cytochromes P450, glutathione S-transferases and Ghanaian medicinal plants, Food Chem. Toxicol., 46, 3598-3603.

Appiah-Opong R., Commandeur JNM., Istyastono E., Bogaards JJ., and Vermeulen NPE., 2009, Inhibition of human glutathione S-transferases by curcumin and analogues, Xenobiotica, 39, 302-311.

Appiah-Opong R., Commandeur JNM., van Vugt-Lussenburg, B., and Vermeulen, N.P.E., 2007, Inhibition of human recombinant cytochrome P450s by curcumin and curcumin decomposition

products, Toxicology, 235, 83-91.

Appiah-Opong R., de Esch I., Commandeur, J.N.M., Andarini, M., and Vermeulen, N.P.E., 2008. Structure-activity relationships for the inhibition of recombinant human cytochromes P450 by curcumin analogues, Eur. J. Med. Chem., 43, 1621-1631.

Asai A. and Miyazawa T., 2000, Occurrence of orally administered curcuminoid as glucuronide and glucuronide/sulfate conjugates in rat plasma, Life Sci., 67, 2785-2793.

Basnet P. and Skalko-Basnet N., 2011, Curcumin: An anti-inflammatory molecule from a curry spice on the path to cancer treatment, Molecules, 16, 45674598.

ChemAxon, 2009. Marvin Beans 5.2.5.1 (http://www.chemaxon.com/products/marvin/), Budapest. de Graaf C., Kooistra AJ., Vischer HF., Katritch V., Kuijer M., Shiroishi M.,Iwata S., Shimamura T., Stevens RC., de Esch IJP., and Leurs R., 2011, Crystal structure-based virtual screening for fragment-like ligands of the human histamine H receptor, J. Med. Chem., 54, 8195-8206.

de Graaf C., Oostenbrink C., Keizers PHJ., van der Wijst T., Jongejan A., and Vermeulen NPE., 2006, Catalytic site prediction and virtual screening of cytochrome P450 2D6 substrates by consideration of water and rescoring in automated docking, J. Med. Chem., 49, 2417-2430.

de Graaf C., Vermeulen NPE., and Feenstra, K.A., 2005, Cytochrome p450 in silico: An integrative modeling approach, J. Med. Chem., 48, 2725-2755. European Bioinformatics Institute, 2012. ChEBI, 2010 (https://www.ebi.ac.uk/chebi/init.do. Accessed 1 September 2012), Cambridgeshire..

Hoehle SI., Pfeiffer E., Sólyom AM., and Metzler M., 2006, Metabolism of curcuminoids in tissue slices and subcellular fractions from rat liver, J.Agri. Food Chem., 54, 756-764.

Ireson C., Orr S., Jones DJL., Verschoyle R., Lim C., Luo J., Howells L., Plummer S., Jukes R., Williams M., Steward WP., and Gescher A., 2001, Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo , and

evaluation of their ability to inhibit phorbol ester-induced prostaglandin E production, Cancer Res., 61, 1058-1064.

Istyastono EP., Supardjan, and Pranowo HD., 2003, Tautomeri Keto-Enol Kurkumin dan Beberapa Turunan Kurkumin Tersubstitusi pada C-4 : Suatu Kajian Teoritis Berdasarkan Pendekatan Kimia Komputasi, Indo. J. Chem., 14, 107-113.

Komura H. and Iwaki M., 2011, In vitro and in vivo small intestinal metabolism of CYP3A and UGT substrates in preclinical animals species and humans: Species differences, Drug Metab. Rev., 43, 476-498.

Korb O., Stützle T., and Exner TE., 2007, An ant colony optimization approach to flexible protein–ligand docking, Swarm Intelligence, 1, 115-134.

Korb O., Stützle T., and Exner TE., 2009. Empirical scoring functions for advanced protein-ligand docking with PLANTS, J. Chem. Inf. Model., 49, 84-96.

Kunwar A., Barik A., Mishra B., Rathinasamy K., Pandey R., and Priyadarsini KI., 2008, Quantitative cellular uptake, localization and cytotoxicity of curcumin in normal and tumor cells, BBA, 1780, 673-679.

Lill MA. and Danielson ML., 2011, Computeraided drug design platform using PyMOL, J. Comput.-Aided Mol. Des., 25, 13-19.

Marcou G. and Rognan D., 2007, Optimizing fragment and scaffold docking by use of molecular interaction fingerprints, J. Chem. Inf. Model., 47, 195-207.

O’Boyle NM., Banck M., James CA., Morley C., Vandermeersch T., and Hutchison G.R., 2011, Open Babel: An open chemical toolbox, J.Cheminform., 3, 33-46.

R Development Core Team, 2008, R: A Language and Environment for Statistical Computing (http://www.r-project.org),

Vienna. Radifar M., 2012. PyPLIF 0.1.1 (http://code.google.com/p/pyplif/ Accessed 31 August 2012).

Rendic S., 2002, Summary of information on human CYP enzymes: human P450 metabolism data, Drug Metab. Rev., 34, 83-448.

Sevrioukova IF. and Poulos TL., 2012, Structural and mechanistic insights into the interaction of cytochrome P450 3A4 with bromoergocryptine, a type I ligand. J. Biol. Chem., 287, 3510-3517.

Tamvakopoulos C., Sofianos ZD., Garbis SD., and Pantazis, P., 2007, Analysis of the in vitro metabolites of diferuloylmethane (curcumin) by liquid chromatography-tandem mass spectrometry on a hybrid quadrupole linear ion trap system: Newly identified metabolites, Eur. J. Drug Metab.

Pharmacokinet., 32, 51-57.

ten Brink T. and Exner TE., 2009, Influence of protonation, tautomeric, and stereoisomeric states on protein-ligand docking results, J. Chem. Inf. Model., 49, 15351546.

Tiwari R., Mahasenan K., Pavlovicz R., Li, C., and Tjarks W., 2009, Carborane clusters in computational drug design: A comparative docking evaluation using AutoDock, FlexX, Glide, and Surflex, J. Chem. Inf. Model., 49, 1581-1589.

Yuniarti N., Ikawati Z., and Istyastono EP., 2011, The importance of ARG513 as a hydrogen bond anchor to discover COX-2 inhibitors in a virtual screening campaign, Bioinformation, 6, 164-166.




DOI: http://dx.doi.org/10.14499/indonesianjpharm24iss2pp75-85

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