Computational Analysis of Physicochemical, Pharmacokinetic and Toxicological Properties of Deoxyhypusine Synthase Inhibitors with Antimalarial Activity


Malaria is a parasitic disease which has as etiological agents protozoa of the genus Plasmodium prevalent in tropical countries. The appearance of Plasmodium strains resistant to artemisinin has become necessary the development of new drugs using computational tools to combat this epidemic. Diverse transporter proteins can act as antimalarials targets, thereby being the enzyme deoxyhypusine synthase a promising antimalarial target. The present study aimed to investigate 15 most active inhibitors of deoxyhypusine synthase target, deposited in databases Binding DB, in order to trace a pattern of physicochemical, pharmacokinetic and toxicological properties of the inhibitors for this enzyme and propose new inhibitors of deoxyhypusine synthase target. The physicochemical properties were obtained according to the Lipinski parameters to evaluate oral absorption. Based on the certain properties were proposed three new inhibitors (A, B and C). The ADME/Tox properties were calculated for new inhibitors compared with results of the selected compounds. The fifteen inhibitors for oral administration showed satisfactory results, because they have adapted to the Lipinski parameters. In relation to the penetration of the blood-brain barrier the inhibitors analyzed showed penetration values less than 1, and ranged from 0.0411815 to 0.481764, being that the compound 1 showed value of CBrain/CBlood = 0.135467. Compound B showed a higher strength in plasma protein binding in relation to the compound 1, having a variation be-tween them of ±1.489344. Therefore, the compound B would present a longer halflife compared with compound 1. The proposed compounds showed positive and satisfactory results, being able to reach less adverse effects related to the central nervous system depending of administered dose.

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Silva, N. , Gonçalves, L. , Duarte, J. , Silva, J. , Santos, C. , Braga, F. , Silva, R. , Costa, J. , Hage-Melim, L. and dos Santos, C. (2014) Computational Analysis of Physicochemical, Pharmacokinetic and Toxicological Properties of Deoxyhypusine Synthase Inhibitors with Antimalarial Activity. Computational Molecular Bioscience, 4, 47-57. doi: 10.4236/cmb.2014.44006.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Santos, C.B.R. (2014) Desenvolvimento Racional de Fármacos Antimaláricos Derivados da Artemisinina usando Métodos Computacionais SAR e QSAR. Dr. Thesis, Federal University of Amazonas, Brazil.
[2] Santos, C.B.R., Lobato, C.C., Vieira, J.B., Brasil, D.S.B., Brito, A.U., Macêdo, W.J.C., Carvalho, J.C.T. and Pinheiro, J.C. (2013) Evaluation of Quantum Chemical Methods and Basis Sets Applied in the Molecular Modeling of Artemisinin. Computational Molecular Bioscience, 3, 66-79.
[3] Santos, C.B.R., Lobato, C.C., Braga, F.S., Morais, S.S.S., Santos, C.F., Fernandes, C.P., Brasil, D.S.B., Hage-Melim, L.I.S., Macêdo, W.J.C. and Carvalho, J.C.T. (2014) Application of Hartree-Fock Method for Modeling of Bioactive Molecules Using SAR and QSPR. Computational Molecular Bioscience, 4, 1-24.
[4] Guiguemde, W.A., Shelat, A.A., Bouck, D., Duffy, S., Crowther, G.J., Davis, P.H., Smithson, D.C., Connelly, M., Clark, J., Zhu, F., Jiménez-díaz, M.B., Martinez, M.S., Wilson, E.B., Tripathi, A.K., Gut, J., Sharlow, E.R., Bathurst, I., Mazouni, F.E., Fowble, J.W., Forquer, I., Mcginley, P.L., Castro, S., Angulo-Barturen, I., Ferrer, S., Rosenthal, P.J., Derisi, J.L., Sullivan, D.J., Lazo, J.S., Roos, D.S., Riscoe, M.K., Phillips, M.A., Rathod, P.K., Van Voorhis, W.C., Avery, V.M. and Guy, R.K. (2010) Chemical Genetics of Plasmodium falciparum. Nature, 465, 311-315.
[5] Kaiser, A., Ulmer, D., Goebel, T., Holzgrabe, U., Saeftel, M. and Hoerauf, A. (2006) Inhibition of Hypusine Biosynthesis in Plasmodium: A Possible, New Strategy in Prevention and Therapy of Malaria. Mini-Reviews in Medicinal Chemistry, 6, 1231-1241.
[6] Inbar, Y., Schneidman-duhovny, D., Dror, O., Nussinov, R. and Wolfson, H.J. (2007) Deterministic Pharmacophore Detection via Multiple Flexible Alignment of Drug-Like Molecules. Lecture Notes in Computer Science, 3692, 423- 434.
[7] (2012) Discovery Studio Visualizer Software, Version 4.0.
[8] Schneidman-Duhovny, D., Dror, O., Inbar, Y., Nussinov, R. and Wolfson, H.J. (2008) PharmaGist: A Webserver for Ligand-Based Pharmacophore Detection. Nucleic Acids Research, 36, 223-228.
[9] Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J. (2001) Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Advanced Drug Delivery Reviews, 23, 3-26.
[10] Yamashita, S., Furubayashi, T., Kataoka, M., Sakane, T., Sezaki, H. and Tokuda, H. (2000) Optimized Conditions for Prediction of Intestinal Drug Permeability Using Caco-2 Cells. European Journal of Pharmacology, 10, 195-204.
[11] Advanced Chemistry Development, Inc. (2010) ACD/Chemsketch Freware, Version 12.00. Toronto.
[12] Wulfsberg, G. (1987) Principles of Descritive Chemistry. Broks/Cole Publishing, Monterey, 23.
[13] Postigo, M.P., Guido, R.V.C., Castilho, M.S., Pitta, I.R., Albuquerque, J.F.C., Oliva, G. and Andricopulo, A.D. (2010) Discovery of New Inhibitors of Schistosoma mansoni PNP by Pharmacophore-Based Virtual Screening. Journal of Chemical Information and Modeling, 50, 1693-1705.
[14] Zhao, Y.H., Le, J., Abraham, M.H., Hersey, A., Eddershaw, P.J., Luscombe, C.N., Butina, D., Beck, G., Sherborne, B., Cooper, I. and Platts, J.A. (2001) Evaluation of Human Intestinal Absorption Data and Subsequent Derivation of a Quantitative Structure-Activity Relationship (QSAR) with the Abraham Descriptors. Journal of Pharmaceutical Sciences, 90, 749-784.
[15] Balimane, P.V., Chong, S. and Morrison, R.A. (2000) Current Methodologies Used for Evaluation of Intestinal Permeability and Absorption. Journal of Pharmacological and Toxicological Methods, 44, 301-312.
[16] Yazdanian, M., Glynn, S.L., Wright, J.L. and Hawi, A. (1998) Correlating Partitioning and Caco-2 Cell Permeability of Structurally Diverse Small Molecular Weight Compounds. Pharmaceutical Research, 15, 1490-1494.
[17] Irvine, J.D., Takahashi, L., Lockhart, K., Cheong, J., Tolan, J.W., Selick, H.E. and Grove, J.R. (1999) MDCK (Madin-Darby Canine Kidney) Cells: A Tool for Membrane Permeability Screening. Journal of Pharmaceutical Sciences, 88, 28-33.
[18] Singh, S. and Singh, J. (1993) Transdermal Drug Delivery by Passive Diffusion and Iontophoresis: A Review. Medicinal Research Reviews, 13, 569-621.
[19] Godin, D.V. (1995) Pharmacokinetics: Disposition and Metabolism of Drugs. In: Munson, P.L., Mueller, R.A. and Breese, G.R., Eds., Principles of Pharmacology: Basic Concepts and Clinical Applications, Chapman & Hall, New York, 39-84.
[20] Pratt, W.B. and Taylor, P. (1990) Principles of Drug Action: The Basis of Pharmacology. 3th Edition, Churchill Livingstone, New York.
[21] Brunton, L.L. (2012) Goodman & Gilman: As Bases Farmacológicas da Terapêutica. 12th Edition, McGraw-Hill, Rio de Janeiro.
[22] Banks, W.A. (2010) Blood-Brain Barrier as a Regulatory Interface. Forum of Nutrition, 63, 102-110.
[23] Bemis, G.W. and Murcko, M.A. (1999) Designing Libraries with CNS Activity. Journal of Medicinal Chemistry, 42, 4942-4951.
[24] Ma, X., Chen, C. and Yang, J. (2005) Predictive Model of Blood-Brain Barrier Penetration of Organic Compounds. Acta Pharmacologica Sinica, 26, 500-512.
[25] Ames, B.N., Gurney, E.G., Miller, J.A. and Bartsch, H. (1972) Carcinogens as Frameshift Mutagens: Metabolites and Derivatives of 2-Acetylaminofluorene and Other Aromatic Amine Carcinogens. Proceedings of the National Academy of Sciences of the United States of America, 69, 3128-3132.
[26] Woo, Y.T. (2003) Mechanisms of Action of Chemical Carcinogens, and Their Role in Structure-Activity Relationships (SAR) Analysis and Risk Assessment. In: Benigni, R., Ed., Quantitative Structure-Activity Relationship (QSAR) Models of Mutagens and Carcinogens, CRC Press, Boca Raton, 41-80.
[27] Vieira, J.B., Braga, F.S., Lobato, C.C., Santos, C.F., Costa, J.S., Bittencourt, J.A.H.M., Brasil, D.S.B., Hage-Melim, L.I.S., Macêdo, W.J.C., Carvalho, J.C.T. and Santos, C.B.R. (2014) A QSAR, Pharmacokinetic and Toxicological Study of New Artemisinin Compounds with Anticancer Activity. Molecules, 19, 10670-10697.

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