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Article
Author(s)

Carol V. Mesa, Gustavo A. Blandón, Diana L. Muñoz, Carlos E. Muskus, Andrés F. Flórez, Rodrigo Ochoa, Iván D. Vélez and Sara M. Robledo*

Affiliation(s)

PECET, Medical Research Institute, School of Medicine, University of Antioquia, Medellín 050010, Colombia

ABSTRACT

The research on discovery and development of new treatments for cutaneous leishmaniasis has been declared as priority. Using bioinformatics approaches, this study aimed to identify antileishmanial activity in drugs that are currently used as anti-inflammatory andwound healing by such anti-Leishmania activity was validated by in vitro and in vivo assays. In silico analysis identified 153 compounds from which 87 were selected by data mining of DrugBank database, 22 and 44 were detected by PASS (www.way2drug.com/passonline) and BLAST (http://blast.ncbi.nlm.nih. gov/) alignment, respectively. The majority of identified drugs are used as skin protector, anti-acne, anti-ulcerative (wound healer) or anti-inflammatory and few of them had specific antileishmanial activity. The efficacy as antileishmanial was validated in vitro in 12/23 tested compounds and in all seven compounds that were evaluated in in vivo assays. Notably, this is the first report of antileishmanial activity for adapalene. In conclusion, bioinformatics tools not only can help to reduce time and cost of the drug discovery process but also may increase the chance that candidates identified in silico which have a validated antileishmanial activity by combining different biological properties.

KEYWORDS

Bioinformatic screening, blast, second uses, antileishmanial activity, leishmaniasis.

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References

[1] World Health Organization. 2010. Control of the Leishmaniases: Report of a Meeting of the WHO Expert Commitee on the Control of Leishmaniases. Geneva.

[2] Alvar, J., Croft, S., and Olliaro, P. 2006. “Chemotherapy in the Treatment and Control of Leishmaniasis.” Adv. Parasitol .61: 223-74.

[3] Den Boer, M., Argaw, D., Jannin, J., and Alvar, J. 2011. “Leishmaniasis Impact and Treatment Access.” Clin. Microbiol. Infect. 17 (10): 1471-7.

[4] Jorgensen, W. L. 2004. “The Many Roles of Computation in Drug Discovery.” Science 303 (5665): 1813-8.

[5] Doyle, M. A., Gasser, R. B., Woodcroft, B. J., Hall, R. S., and Ralph, S. A. 2010. “Drug Target Prediction and Prioritization: Using Orthology to Predict Essentiality in Parasite Genomes.” BMC Genomics 11 (1): 222.

[6] Awale, M., Kumar, V., Saravanan, P., and Mohan, C. G. 2010. “Homology Modeling and Atomic Level Binding Study of Leishmania MAPK with Inhibitors.” J. Mol. Model. 16 (3): 475-88.

[7] Keiser, M. J., Setola, V., Irwin, J. J., Laggner, C., Abbas, A. I., Hufeisen, S. J. et al. 2009. “Predicting New Molecular Targets for Known Drugs.” Nature 462 (7270): 175-81.

[8] Bredel, M., and Jacoby, E. 2004. “Chemogenomics: An Emerging Strategy for Rapid Target and Drug Discovery.” Nat. Rev. Genet. 5 (4): 262-75.

[9] Ekins, S., Williams, A. J., Krasowski, M. D., and Freundlich, J. S. 2011. “In Silico Repositioning of Approved Drugs for Rare and Neglected Diseases.” Drug Discov. Today 16 (7/8): 298-310.

[10] Hopkins, A. L., and Groom, C. R. 2002. “The Druggable Genome.” Nat. Rev. Drug Discov. 1 (9): 727-30.

[11] Kitano, H. 2002. “Computational Systems Biology.” Nature 420 (6912): 206-10.

[12] Peacock, C. S., Seeger, K., Harris, D., Murphy, L., Ruiz, J. C., Quail, M. A. et al. 2007. “Comparative Genomic Analysis of Three Leishmania Species that Cause Diverse Human Disease.” Nat. Genet. 39 (7): 839-47.

[13] Flórez, A. F., Park, D., Bhak, J., Kim, B. C., Kuchinsky, A., Morris, J. H. et al. 2010. “Protein Network Prediction and Topological Analysis in Leishmania Major As a Tool for Drug Target Selection.” Revista BMC Bioinformatics 11 (10): 484.

[14] Ideker, T., Thorsson, V., Ranish, J. A., Christmas, R., Buhler, J., Eng, J. K., and Hood, L. 2001. “Integrated Genomic and Proteomic Analyses of a Systematically Perturbed Metabolic Network.” Science 292 (5518): 929-34.

[15] Ideker, T., Galitski, T., and Hood, L. 2001. “A New Approach to Decoding Life: Systems Biology.” Annu. Rev. Genomics Hum. Genet. 2 (1): 343-72.

[16] Goel, R. K., Singh, D., Lagunin, A., Poroikov, V. 2011. “PASS-assisted Exploration of New Therapeutic Potential of Natural Products.” Med. Chem. Res. 20 (9):1509-14.

[17] Moreno-Hagelsieb, G., and Latimer, K. 2008. “Choosing BLAST Options for Better Detection of Orthologs AsReciprocal Best Hits. Bioinformatics.” Bioinformatics 24 (3): 319-24.

[18] Chang, K. T., and Dwyer, D. M. 1978. “Leishmania Donovani. Hamster Macrophage Interactions in Vitro: Cell Entry, Intracellular Survival, and Multiplication of Amastigotes.” J. Exp. Med. 147 (2): 515-30.

[19] Insuasty, B., Ramírez, J., Becerra, D., Echeverry, C., Quiroga, J., Abonia, R. et al. 2015. “An Efficient Synthesis of New Caffeine-based Chalcones, Pyrazolines and Pyrazolo[3,4-b][1,4]diazepines As Potential Antimalarial, Antitrypanosomal and Antileishmanial Agents.” Eur. J. Med. Chem. 93: 401-13.

[20] Ahmed, S. A., Gogal, R. M. J., and Walsh, J. E. 1994. “A New Rapid and Simple Non-radioactive Assay to Monitor and Determine the Proliferation of Lymphocytes: An Alternative to [3H]thymidineIncorporation Assay.” J. Immunol. Methods 170 (2): 211-24.

[21] Finney, J. D. 1978. “Statistical Method in Biological Assay.” London: Charles Griffin & Co. Ltd, 3ed, pp. 508.

[22] Pulido, S. A., Muñoz, D. L., Restrepo, A. M., Mesa, C. V., Alzate, J. F., Vélez, I. D., and Robledo, S. M. 2012. “Improvement of the Green Fluorescent Protein Reporter System in Leishmania spp. for the in Vitro and in Vivo Screening of Antileishmanial Drugs.” Acta Trop. 122 (1): 36-45.

[23] Varela, R. E., Muñoz, D. L., Robledo, S. M., Kolli, B. K., Dutta, S., Chang, K. P., and Muskus, C. 2009. “Leishmania (Viannia) Panamensis: An in Vitro Assay Using the Expression of GFP for Screening of Antileishmanial Drug.” Exp. Parasitol. 122 (2): 134-9.

[24] Robledo, S. M., Carrillo, L. M., Daza, A., Restrepo, A. M., Muñoz, D. L., Tobón, J. et al. 2012. “Cutaneous Leishmaniasis in the Dorsal Skin of Hamsters: AUseful Model for the Screening of Antileishmanial Drugs.” J. Vis. Exp. (62), pii: 3533, doi: 10.3791/3533.

[25] Van der Meer, C., and Versluijs-Broers, J. A. 1986. “Trypanosoma Brucei and T. Vivax: Salicylhydroxamic Acid and Glycerol Treatment of Acute and Chronically Infected Rats.” Exp. Parasitol. 62 (1): 98-113.

[26] Titus, R. G., Marchand, M., Boon, T., Louis, J. A. 1985. “A Limiting Dilution Assay for Quantifying Leishmania Major in Tissues of Infected Mice.” Parasite Immunol. 7 (5): 545-55.

[27] Reimão, J. Q., Colombo, F. A., Pereira-Chioccola, V. L., and Tempone, A. G. 2011. “In Vitro and Experimental Therapeutic Studies of the Calcium Channel Blocker Bepridil: Detection of Viable Leishmania (L.) Chagasi by Real-Time PCR.” Exp. Parasitol. 128 (2): 111-5.

[28] Fisher, J. E., Rodan, G. A., and Reszka, A. A. 2000. “In Vivo Effects of Bisphosphonates on the Osteoclast Mevalonate Pathway.” Endocrinology 141 (12): 4793-6.

[29] Rogers, M. J., Gordon, S., Benford, H. L., Coxon, F. P., Luckman, S. P., Monkkonen, J., and Frith, J. C. 2000. “Cellular and Molecular Mechanisms of Action of Bisphosphonates.” Cancer 88 (12 Suppl): 2961-78.

[30] Mukherjee, P., Desai, P. V., Srivastava, A., Tekwani, B. L., and Avery, M. A. 2008. “Probing the Structures of Leishmanial Farnesyl Pyrophosphate Synthases: Homology Modeling and Docking Studies.” J. Chem. Inf. Model. 48 (5): 1026-40.

[31] Ortiz-Gómez, A., Jiménez, C., Estévez, A. M., Carrero-Lérida, J., Ruiz-Pérez, L. M., and González-Pacanowska, D. “Farnesyl Diphosphate Synthase is a Cytosolic Enzyme in Leishmania Major Promastigotes and its Overexpression Confers Resistance to Risedronate.” Eukaryot. Cell 5 (7): 1057-64.

[32] Bikowski, J. B. 2005. “Mechanisms of the Comedolytic and Anti-inflammatory Properties of Topical Retinoids.” J. Drugs Dermatol. 4 (1): 41-7.

[33] Mackrides, P. S., and Shaughnessy, A. F. 1996. “Azelaic Acid Therapy for Acne.” Am Fam Physician 54: 2457-9.

[34] Charnock, C., Brudeli, B., and Klaveness, J. 2004. “Evaluation of the Antibacterial Efficacy of Diesters of Azelaic Acid.” Eur. J. Pharm. Sci. 21 (5): 589-96.

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