In-silico Antimalarial Study of Monocarbonyl Curcumin Analogs and Their 2,4-Dinitro Phenylhydrazones Using the Inhibition of Plasmepsin II as Test Model

Olatomide A. Fadare^1, , Ezekiel O.Iwalewa², Craig A. Obafemi¹ and Feyisola P. Olatunji³

¹Department of Chemistry, Obafemi Awolowo University, Ile-Ife, Nigeria

²Department of Pharmacology, University of Ibadan, Ibadan, Nigeria

³Department of Chemistry, Washington State University, Pullman, U.S.A.

Cite this paper:
Olatomide A. Fadare, Ezekiel O.Iwalewa, Craig A. Obafemi and Feyisola P. Olatunji. In-silico Antimalarial Study of Monocarbonyl Curcumin Analogs and Their 2,4-Dinitro Phenylhydrazones Using the Inhibition of Plasmepsin II as Test Model. American Journal of Pharmacological Sciences. 2017; 5(2):18-24. doi: 10.12691/ajps-5-2-1

Abstract

A well-known component of the Indian spice turmeric, curcumin, has received a lot of attention in recent years as a potential antimalarial agent but the inherent problems associated with low bioavailabilty tends to limit its applicability. The bioavailability is linked to its low solubility in water and its rapid break down in the blood plasma. In this study, we have proposed the use of synthetic analogs of curcumin and their derivatives which are expected to be less prone to degradation in the blood plasma as possible antimalarials. The binding affinity of monocarbonyl analogs of curcumin and their 2,4-dinitrophenylhydrazone derivatives for the chain A domain of plasmepsin II, one of the key enzymes involved in hemoglobin digestion in the food vacuole of the malaria parasite was determined by computational docking analysis, performed using Auto Dock Vina 1.1.2, pymol and Chem 3D ultra 12.0. The binding energies of the 20 compounds studied was compared with that of pepstatin A (a known inhibitor of plasmepsin II), curcumin and chloroquine. The 3D structure of the protein was obtained from the protein data bank (PDB ID:1M43), the compounds’ 3D structure was generated with the Chem 3D ultra 12.0 and visualization done with pymol. Out of the 20 compounds docked with plasmepsin II, 17 had binding energies higher than that of pep A (-32.6, kJ/mol) and 19 of the compounds had binding energies higher than that of curcumin (30.96, kJ/mol). The docked compounds, 5b, 6b and 7b had the highest binding energies (-44.73 kJ/mol, -42.64 kJ/mol and -41.80 kJ/mol respectively). It is expected that the compounds with binding energies higher than that of pep A may be considered for further antimalarial studies in-vitro and in-vivo.

Keywords:
monocarbonyl curcumin analog 24-dinitrophenyl hydrazone low bioavailability plasmepsin II pepstatin A

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References:

[1]	W.H.O. (2010) World Malaria Report 2010. Available at: http://www.who.int/malaria/world_malaria_report_2010/worldmalariareport2010.pdf. Accessed: March/2011.
[2]	Mishra, K., Dash A.P., Swain B.K., Dey N., “Anti-malarial activities of Andrographis paniculata and Hedyotis corymbosa extracts and their combination with curcumin” Malar. J., 8: 26, 2009.
[3]	Mulabagal V., Calderon A.I., “Development of binding assays to screen ligands for Plasmodium falciparum thioredoxin and glutathione reductases by ultrafiltration and liquid chromatography/mass spectrometry” J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 878: 987-93, 2010.
[4]	Nandakumar, D.N., Nagaraj, V.A., Vathsala, P.G., Rangarajan, P., Padmanaban G. “Curcumin-artemisinin combination therapy for malaria” Antimicrob. Agents Chemother. 50 (2006) 1859-60.
[5]	Reddy R.C., Vatsala P.G., Keshamouni V.G., Padmanaban G., Rangarajan P.N. “Curcumin for malaria therapy”. Res. Biochem. Biophys Commun.; 326: 472-4, 2005.
[6]	Aggarwal B.B., Sundaram C., Malani N., Ichikawa H. “Curcumin: The Indian Solid Gold”. Adv. Exp. Med. Biol, 595: 1-75, 2007.
[7]	Anand P., Kunnumakkara A.B., Newman R., Aggarwal B.B. “Bioavailability of Curcumin: Problems and Promises”. Molecular Pharmaceutics; 4(6): 807-18. 2007
[8]	Nayak A.P., Tiyaboonchai W., Patankar S., Madhusudhan B., Souto E.B., “Curcuminoids Loaded Lipid Nanoparticles: Novel Approach Towards Malaria Treatment” Colloids Surf. B: Biointerfaces, 81: 263-73, 2010.
[9]	Akhtar F., Rizvi M.M., Kar S.K. “Oral Delivery of Curcumin Bound to Chitosan Nanoparticles Cured Plasmodium yoelii Infected Mice” Biotechnol. Adv; 30: 310-20, 2012.
[10]	Ahmed K., Li Y., McClements D.J., Xiao H. “Nanoemulsion - and Emulsion-based Delivery Systems for Curcumin: Encapsulation and Release properties” Food Chem, 132: 799-807, 2012.
[11]	Yu, H., Huang. Q. “Improving the Oral bioavailability of Curcumin Using Novel Organogel-based Nanoemulsions”. J. Agric. Food Chem; 60: 5373-9, 2012.
[12]	Desai, K. Curcumin Cyclodextrin Combination for Preventing or Treating Various Diseases. Patent US 2010/0779103.
[13]	Maiti, K., Mukherjee, K., Gantait A, Saha B.P., Mukherjee P.K. “Curcumin Phospholipid Complex: Preparation, Therapeutic Evaluation and Pharmacokinetic Study in Rats”. Int. J. Pharm; 330: 155-63, 2007.
[14]	Seo, S.W., Han, H.K., Chun M.K., Choi, H.K. “Preparation and Pharmacokinetic Evaluation of Curcumin Solid Dispersion using Solutol HS15 as a Carrier”. Int. J. Pharm; 424: 18-25, 2012.
[15]	Yallapu, M.M., Jaggi, M., Chauhan S.C. “Curcumin Nano formulations: A Future Nanomedicine for Cancer”. Drug Discov. Today; 17: 71-81, 2012.
[16]	Marczylo T.H., Verschoyle, R.D., Cooke D.N., Morazzoni, P., Steward, W.P., Gescher, A.J. “Comparison of Systemic Availability of Curcumin with that of Curcumin Formulated with Phosphatidylcholine” Cancer Chemotherapy and Pharmacology; 60(2): 171-7, 2007.
[17]	Cui, J., Yu, B., Zhao, Y., Zhu, W., Li, H., Lou, H., Zhai, G. “Enhancement of Oral Absorption of Curcumin by Self-microemulsifying Drug Delivery Systems” Int. J. Pharm; 371: 148-55, 2009.
[18]	Setthacheewakul, S., Mahattanadul, S., Phadoongsombut N., Pichayakorn, W., Wiwattanapatapee, R., “Development and Evaluation of Self-microemulsifying Liquid and Pellet Formulations of Curcumin, and Absorption Studies in Rats” Eur. J. Pharm. Biopharm; 76: 475-85, 2010.
[19]	Yan T.D., Kim, J.A., Kwak, M.K., Yoo, B.K., Yong C.S., Choi, H.G. “Enhanced oral Bioavailability of Curcumin via a Solid Lipid-based Self-emulsifying Drug Delivery System Using a Spray-drying Technique”. Biol. Pharm. Bull; 34: 1179-86, 2011.
[20]	Banerjee R., Liu, J., Beatty, W., Pelosof, L., Klemba, M. and Goldberg D.E. “Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine”. Proceedings of the National Academy of Sciences of the United States of America; 99: 990-95, 2002.
[21]	Gluzman, I.Y., Francis, S.E., Oksman, A., Smith, C.E., Duffin, K.L. and Goldberg, D.E. “Order and specificity of the Plasmodium falciparum hemoglobin degradation pathway”. Journal of Clinical Investigation; 93(4): 1602-08, 1994.
[22]	Dame, J.B., Reddy, G.R., Yowell, C.A., Dunn, B.M., Kay, J. and Berry, C. “Sequence, expression and modelled structure of an aspartic proteinase from the human malaria parasite:Plasmodium falciparum”. Molecular and Biochemical Parasitology. vol. 64, no. 2, pp. 177-90. 1994.
[23]	Humphreys M.J., Moon, R.P., Klinder A. et al. “The aspartic proteinase from the rodent parasite Plasmodium berghei as a potential model for plasmepsins from the human malaria parasite, “Plasmodium falciparum”. FEBS Letters; 463(1-2): 43-8, 1999.
[24]	Salas, F., Fichmann, J., Lee, G.K., Scott, M.D. and Rosenthal P.J. “Functional expression of falcipain, a Plasmodium falciparum cysteine proteinase, supports its role as a malarial hemoglobinase”. Infection and Immunity; 63(6): 2120-2125, 1995.
[25]	Sijwali, P.S., Kato, K., Seydel K.B. et al. “Plasmodium falciparum cysteine protease falcipain-1 is not essential in erythrocytic stage malaria parasites”. Proceedings of the National Academy of Sciences of the United States of America; 101(23): 8721-26, 2004.
[26]	Shenai, B.R., Sijwali, P.S., Singh, A. and Rosenthal, P.J., “Characterization of native and recombinant falcipain-2, a principal trophozoite cysteine protease and essential hemoglobinase of Plasmodium falciparum”. Journal of Biological Chemistry; 275(37): 29000-010, 2000.
[27]	Sijwali, P.S., Shenai, B.R., Gut, J., Singh, A. and Rosenthal, P.J. “Expression and characterization of the Plasmodium falciparum haemoglobinase falcipain-3”. Biochemical Journal; 360(2): 481-89, 2001.
[28]	Eggleson, K.K., Duffin, K.L. and Goldberg, D.E. “Identification and characterization of falcilysin, a metallopeptidase involved in hemoglobin catabolism within the malaria parasite Plasmodium falciparum”. Journal of Biological Chemistry; 274(45): 32411-417. 1999.
[29]	Klemba, M., Gluzman, I. and Goldberg, D.E., “A Plasmodium falciparum dipeptidyl aminopeptidase I participates in vacuolar hemoglobin degradation”. Journal of The Biological Chemistry; 279(41): 43000–007. 2004.
[30]	Gluzman, I.Y., Francis, S.E., Oksman, A., Smith, C.E., Duffin, K.L and Goldberg, D.E. “Order and specificity of the Plasmodium falciparum haemoglobin degradation pathway”. The Journal of Clinical Investigation; 93: 1602-08.1994.
[31]	Goldberg, D.E., Slater, A.F., Beavis, R., Chait, B., Cerami A. and Henderson, G.B. “Hemoglobin degradation in the human malaria pathogen Plasmodium falciparum: a catabolic pathway initiated by a specific aspartic protease” The Journal of Experimental Medicine; 173: 961-69.1991
[32]	Goldberg, D.E. “Hemoglobin degradation in Plasmodium-infected red blood cells”. Seminars in Cell Biology; 4: 355-61, 1993.
[33]	Eggleson, K.K., Duffin, K.L. and Goldberg, D.E. “Identification and characterization of falcilysin, a metallopeptidase involved in haemoglobin catabolism within the malaria parasite Plasmodium falciparum”. The Journal of Biological Chemistry; 274: 32411-17, 1991.
[34]	Francis, S.E., Gluzman, I.Y., Oksman, A., Banerjee D. and Goldberg, D.E. “Characterization of native falcipain, an enzyme involved in Plasmodium falciparum hemoglobin degradation”. Molecular and Biochemical Parasitology; 83: 189-200. 1996.
[35]	Le Bonniec, S., Deregnaucourt, C., Redeker, V., Banerjee, R., Grellier, P., Goldberg D.E. and Schrevel. J. “Plasmepsin II, an acidic hemoglobinase from the Plasmodium falciparum food vacuole, is active at neutral pH on the host erythrocyte membrane skeleton”. The Journal of Biological Chemistry; 274: 14218-223. 1999.
[36]	Blackman, M.J. “Malarial proteases and host cell egress: an ‘emerging’ cascade”. Cellular Microbiology; 10: 1925-34. 2008.
[37]	Silva A.M., Lee, A.Y., Gulnik, S.V., Maier, P., Collins, J., Bhat, T.N., Collins, P.J., Cachau, R.E., Luker, K.E., Gluzman, I.Y., Francis, S.E., Oksman, A., Goldberg, D.E., and Erickson, J.W. “Structure and inhibition of plasmepsin II, a hemoglobin-degrading enzyme from Plasmodium falciparum”. Proceedings of the National Academy of Sciences of the United States of America; 93(19): 10034-39.1996.
[38]	Asojo, O.A., Gulnik, S.V., Afonina, E. et al. “Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from Plasmodium falciparum” Journal of Molecular Biology; 327(1), 173-81. 2003.
[39]	Asojo, O.A., Afonina, E., Gulnik S.V. et al. “Structures of ser205 mutant plasmepsin II from Plasmodium falciparum at 1.8 A in complex with the inhibitors rs367 and rs370.” Acta Crystallographica Section D; 58(12); 2001-008. 2002
[40]	Boss, C., Richard-Bildstein, S., Weller T. et al. “Inhibitors of the Plasmodium falciparum parasite aspartic protease plasmepsin II: as agents”. Current Medicinal Chemistry; 10: 883-907. 2003.
[41]	Ersmark, K., Feierberg, I., Bjelic S. et al. “C-symmetric inhibitors of Plasmodium falciparum plasmepsin II: synthesis and theoretical predictions”. Bioorganic and Medicinal Chemistry; 11(17): 3723-33. 2003.
[42]	Ersmark, K., Feierberg, I., Bjelic S. et al. “Potent inhibitors of the Plasmodium falciparum enzymes plasmepsin I and II devoid of cathepsin D inhibitory activity”. Journal of Medicinal Chemistry; 47(1): 110-122.
[43]	Kiso, A., Hidaka, K., Kimura T. et al. “Search for substrate based inhibitors fitting the S2’ space of malarial aspartic protease plasmepsin II”. Journal of Peptide Science; 10(11): 641-47. 2004.
[44]	Ersmark, K., Samuelsson, B. and Hallberg, A. “Plasmepsins as potential targets for new antimalarial therapy”. Medicinal Research Reviews; 26(5): 626-66. 2006
[45]	Rosenthal, P.J. “Plasmodium falciparum: effects of proteinase inhibitors on globin hydrolysis by cultured malaria parasites” Experimental Parasitology; 80: 272-81. 1995.
[46]	Francis, S.E, Gluzman, I.Y., Oksman, A., Knickerbocker, A., Mueller, R., Bryant, M.L., Sherman, D.R., Russell D.G., Goldberg, D.E. Molecular characterization and inhibition of a Plasmodium falciparum aspartic hemoglobinase. The EMBO Journal 1994; 13: 306-17.
[47]	Nezami, A., Kimura, T., Hidaka, K., Kiso, A., Liu, J., Kiso, Y., Goldberg, D.E., Freire, E. “High-affinity inhibition of a family of Plasmodium falciparum proteases by a designed adaptive inhibitor”. Biochemistry; 42, 8459-64. 2003.
[48]	Wyatt, D.W. and Berry, C. “Activity and inhibition of plasmepsin IV, a new aspartic proteinase from the malaria parasite, Plasmodium falciparum” FEBS Letters; 513: 159-62. 2002.
[49]	Westling, J., Yowell, C.A., Majer, P., Erickson, J.W., Dame J. and Dunn, B.M. “Plasmodium falciparum, P. vivax, and P. malariae: a comparison of the active site properties of plasmepsins cloned and expressed from three different species of the malaria parasite” Experimental Parasitology ; 87: 185-93.1997.
[50]	Prade, L., Jones, A.F., Boss, C.R., Bildstein, S. Meyer, S., Binkert, C. and Bur, D. “X-ray structure of plasmepsin II complexed with a potent achiral inhibitor”. The Journal of Biological Chemistry; 280: 23837-843, 2005.
[51]	Johansson, P.O., Lindberg, J., Blackman, M.J., Kvarnstrom, I., Vrang, L., Hamelink, E., Hallberg, A., Rosenquist A. and Samuelsson, B., “Design and synthesis of potent inhibitors of plasmepsin I and II: X-ray crystal structure of inhibitor in complex with plasmepsin II”. Journal of Medicinal Chemistry; 48: 4400-09. 2005.
[52]	Bjelic, S., Nervall, M., Gutierrez-deTeran, H., Ersmark, K., Hallberg A. and Aqvist, J. “Computational inhibitor design against malaria plasmepsins”. Cellular and Molecular Life Sciences; 64: 2285-2305. 2007
[53]	Azim, M.K., Ahmed, W., Khan I.A., Rao N.A. and Khan, K.M. “Identification of acridinyl hydrazides as potent aspartic protease inhibitors”. Bioorganic & Medicinal Chemistry Letters; 18: 3011-15.2008.
[54]	Blum, A., Bottcher, J., Sammet, B., Luksch, T., Heine, A., Klebe, G., Diederich, W.E. “Achiral oligoamines as versatile tool for the development of aspartic protease inhibitors”. Bioorganic & Medicinal Chemistry 16: 8574-86. 2008.
[55]	Cunico, W., Gomes, C.R., Facchinetti, V., Moreth, M., Penido, C., Henriques, M.G., Varotti, F.P., Krettli, L.G., Krettli, A.U, da Silva, F.S., Caffarena E.R. and de Magalhaes, C.S. “Synthesis, antimalarial evaluation and molecular modeling studies of hydroxyl ethylpiperazines, potential aspartyl protease inhibitors, part 2”. European Journal of Medicinal Chemistry; 44: 3816-20. 2009.
[56]	Degliesposti, G., Kasam, V., Da Costa, A., Kang, H.K., Kim, N., Kim, D.W., Breton, V., Kim D. and Rastelli, G. “Design and discovery of plasmepsin II inhibitors using an automated workflow on largescale grids”. ChemMedChem; 4: 1164-73. 2009.
[57]	Fah, C., Hardegger, L.A., Baitsch, L., Schweizer, W.B., Meyer S., Bur, D. and Diederich F. “New organofluorine building blocks: inhibition of the malarial aspartic proteases plasmepsin II and IV by alicyclic alpha,alpha-difluoroketone hydrates”. Organic and Biomolecular Chemistry; 7: 3947-57. 2009.
[58]	Friedman R. and Caflisch, A. “Discovery of plasmepsin inhibitors by fragment-based docking and consensus scoring”. ChemMedChem; 4: 1317-26. 2009.
[59]	Hidaka, K., Kimura, T., Ruben, A.J., Uemura, T., Kamiya, M., Kiso, A., Okamoto, T., Tsuchiya, Y., Hayashi, Y., Freire, E. and Kiso, Y. “Antimalarial activity enhancement in hydroxymethylcarbonyl (HMC) isosterebased dipeptidomimetics targeting malarial aspartic protease plasmepsin”. Bioorganic & Medicinal Chemistry 2008; 16: 10049-60.
[60]	Janka, L., Clemente, J., Vaiana, N., Sparatore, A., Romeo S. and Dunn, B.M. “Targeting the plasmepsin 4 orthologs of Plasmodium sp. with “double drug” inhibitors”. Protein and Peptide Letters; 15: 868-73. 2008.
[61]	Kasam, V., Salzemann, J., Botha, M., Dacosta, A., Degliesposti, G., Isea, R., Kim, D., Maass, A., Kenyon, C., Rastelli, G., Hofmann-Apitius M., and Breton, V. “WISDOM-II: screening against multiple targets implicated in malaria using computational grid infrastructures”. Malaria Journal; 8: 88. 2009.
[62]	Luksch, T., Chan, N.S., Brass, S., Sotriffer, C.A., Klebe G. and Diederich, W.E. “Computer-aided design and synthesis of nonpeptidic plasmepsin II and IV inhibitors”. ChemMedChem; 3: 1323-36. 2008.
[63]	Nguyen, J.T., Hamada, Y., Kimura, T. and Kiso, Y. “Design of potent aspartic protease inhibitors to treat various diseases”. Archiv der Pharmazie; 341: 523-35. 2008.
[64]	Orrling, K.M., Marzahn, M.R., Gutierrezde-Teran, H., Aqvist, J., Dunn, B.M. and Larhed, M. “Alpha-Substituted norstatines as the transition-state mimic in inhibitors of multiple digestive vacuole malaria aspartic proteases”. Bioorganic & Medicinal Chemistry; 17: 5933-49. 2009.
[65]	Ramirez, A.R., Guerra, Y., Otero, A., Garcia, B., Berry, C., Mendiola, J., Hernandez-Zanui, A., Chavez Mde, L. “Generation of an affinity matrix useful in the purification of natural inhibitors of plasmepsin II, an antimalarial-drug target”. Biotechnology and Applied Biochemistry 2009; 52: 149-57.
[66]	Rumsh, L.D., Mikhailova, A.G., Mikhura, I.V., Prudchenko, I.A., Chikin, L.D., Mikhaleva, I.I., Kaliberda, E.N., Dergousova, N.I., Mel’nikov E.E. and Formanovskii, A.A “Selective inhibitors of plasmepsin II from Plasmodium falciparum based on pepstatin”. Bioorganicheskaia Khimiia; 34: 739-46. 2009.
[67]	Jiang, S., Prigge, S.T., Wei, L., Gao, Y., Hudson, T.H., Gerena, L., Dame J.B. and Kyle, D.E. “New class of small nonpeptidyl ompounds blocks Plasmodium falciparum development in vitro by inhibiting plasmepsins”. Antimicrobial Agents and Chemotherapy; 45: 2577-84. 2001.
[68]	Weik, S., Luksch, T., Evers, A., Bottcher, J., Sotriffer, C.A., Hasilik, A., Loffler, H.G., Klebe G. and Rademann, J. “The potential of P1 site alterations in peptidomimetic protease inhibitors as suggested by virtual screening and explored by the use of C–C-coupling reagents”. ChemMedChem; 1: 445-57. 2006.
[69]	Carroll C.D. and Orlowski, D. “Screening aspartyl proteases with combinatorial libraries”. Advances in Experimental Medicine and Biology; 436: 375-80. 1998.
[70]	Flotow, H., Leong C.Y. and Buss, A.D. “Development of a plasmepsin II fluorescence polarization assay suitable for high throughput antimalarial drug discovery”. Journal of Biomolecular Screening; 7: 367-371. 2002.
[71]	Dell’Agli, M., Galli, G.V., Corbett, Y., Taramelli, D., Lucantoni, L., Habluetzel, A., Maschi, O., Caruso, D., Giavarini, F., Romeo, S., Bhattacharya D. and Bosisio, E. “Antiplasmodial activity of Punica granatum L. fruit rind”. Journal of Ethology; 125: 279-85. 2009.
[72]	Dell’Agli, M., Galli, G.V., Parapini, S., Basilico, N., Taramelli, D., Said, A., Rashed K. and Bosisio, E. “Antiplasmodial activity of Ailanthus excels”. Fitoterapia; 79: 112-16. 2008.
[73]	Trott, O., Olson, A.J. “AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading” Journal of Computational Chemistry; 31: 455-61. 2010.