Hostname: page-component-586b7cd67f-rdxmf Total loading time: 0 Render date: 2024-11-30T20:28:25.698Z Has data issue: false hasContentIssue false
  • English
  • Français

Drug screening using shape-based virtual screening and in vitro experimental models of cutaneous Leishmaniasis

Published online by Cambridge University Press:  07 October 2020

Camila Cardoso Santos ,
Marcos Meuser Batista ,
Asma Inam Ullah ,
Tummala Rama Krishna Reddy  and
Maria de Nazaré Correia Soeiro Open the ORCID record for Maria de Nazaré Correia Soeiro [Opens in a new window]
Camila Cardoso Santos
Affiliation:
Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), CEP21040-360, Rio de Janeiro, RJ, Brazil
Marcos Meuser Batista
Affiliation:
Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), CEP21040-360, Rio de Janeiro, RJ, Brazil
Asma Inam Ullah
Affiliation:
The Medicines Research Group, School of Health, Sport and Bioscience, College of Applied Health and Communities, University of East London, Stratford Campus, Water Lane, London, UK
Tummala Rama Krishna Reddy
Affiliation:
The Medicines Research Group, School of Health, Sport and Bioscience, College of Applied Health and Communities, University of East London, Stratford Campus, Water Lane, London, UK
Maria de Nazaré Correia Soeiro*
Affiliation:
Laboratory of Cellular Biology (LBC), Oswaldo Cruz Institute (IOC/FIOCRUZ), CEP21040-360, Rio de Janeiro, RJ, Brazil
*
Author for correspondence: Maria de Nazaré Correia Soeiro, E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Cutaneous leishmaniasis (CL) is one of the most disregarded tropical neglected disease with the occurrence of self-limiting ulcers and triggering mucosal damage and stigmatizing scars, leading to huge public health problems and social negative impacts. Pentavalent antimonials are the first-line drug for CL treatment for over 70 years and present several drawbacks in terms of safety and efficacy. Thus, there is an urgent need to search for non-invasive, non-toxic and potent drug candidates for CL. In this sense, we have implemented a shape-based virtual screening approach and identified a set of 32 hit compounds. In vitro phenotypic screenings were conducted using these hit compounds to check their potential leishmanicidal effect towards Leishmania amazonensis (L. amazonensis). Two (Cp1 and Cp2) out of the 32 compounds revealed promising antiparasitic activities, exhibiting considerable potency against intracellular amastigotes present in peritoneal macrophages (IC50 values of 9.35 and 7.25 μm, respectively). Also, a sterile cidality profile was reached at 20 μm after 48 h of incubation, besides a reasonable selectivity (≈8), quite similarly to pentamidine, a diamidine still in use clinically for leishmaniasis. Cp1 with an oxazolo[4,5-b]pyridine scaffold and Cp2 with benzimidazole scaffold could be developed by lead optimization studies to enhance their leishmanicidal potency.

Keywords

Cutaneous leishmaniasisin vitro experimental chemotherapyLeishmania amazonensisshape-based virtual screening
Type
Research Article
Information
Parasitology , Volume 148 , Issue 1 , January 2021 , pp. 98 - 104
Check for updates
Copyright
Copyright © The Author(s) 2020. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Alvar, J, Vélez, ID, Bern, C, Herrero, M, Desjeux, P, Cano, J, Jannin, J and den Boer, M., & WHO Leishmaniasis Control Team (2012) Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE 7, e35671.CrossRefGoogle ScholarPubMed
Bailey, F, Mondragon-Shem, K, Haines, LR, Olabi, A, Alorfi, A, Ruiz-Postigo, JA, Alvar, J, Hotez, P, Adams, ER, Vélez, ID, Al-Salem, W, Eaton, J, Acosta-Serrano, Á and Molyneux, DH (2019) Cutaneous leishmaniasis and co-morbid major depressive disorder: a systematic review with burden estimates. Cutaneous leishmaniasis and co-morbid major depressive disorder: a systematic review with burden estimates. PLoS Neglected Tropical Diseases 13, e0007092.CrossRefGoogle ScholarPubMed
Bilgic-Temel, A, Murrell, DF and Uzun, S (2019) Cutaneous leishmaniasis: a neglected disfiguring disease for women. International Journal of Women's Dermatology 5, 158–165.CrossRefGoogle ScholarPubMed
Cal, M, Ioset, J-R, Fügi, MA, Mäser, P and Kaiser, M (2016) Assessing anti-T. cruzi candidates in vitro for sterile cidality. International Journal for Parasitology: Drugs and Drug Resistance 6, 165–170.Google ScholarPubMed
Canvas (2017) Schrödinger Release 2017–2: Maestro, Schrödinger, LLC, New York, NY.Google Scholar
Caridha, D, Vesely, B, van Bocxlaer, K, Arana, B, Mowbray, CE, Rafati, S, Uliana, S, Reguera, R, Kreishman-Deitrick, M, Sciotti, R, Buffet, P and Croft, SL (2019) Route map for the discovery and pre-clinical development of new drugs and treatments for cutaneous leishmaniasis. International Journal for Parasitology: Drugs and Drug Resistance 11, 106–117.Google ScholarPubMed
Chatelain, E and Ioset, JR (2011) Drug discovery and development for neglected diseases: the DNDi model. Drug Design, Development and Therapy 16, 175–81.Google Scholar
Da Silva, CF, Batista, MM, Mota, RA, de Souza, EM, Stephens, CE, Som, P, Boykin, DW and Soeiro Mde, N (2007) Activity of “reversed” diamidines against Trypanosoma cruzi “in Vitro”. Biochemical Pharmacology 73, 1939–46.CrossRefGoogle Scholar
de Vries, HJ, Reedijk, SH and Schallig, HD (2015) Cutaneous leishmaniasis: recent developments in diagnosis and management. American Journal of Clinical Dermatology 16, 99–109.CrossRefGoogle ScholarPubMed
DNDi Annual report (2018) Making medical history. Available at https://www.dndi.org/wp-content/uploads/2019/07/DNDi_2018_AnnualReport.pdf (Accessed 8 March 2020).Google Scholar
El-Sayed, N, Myler, P, Blandin, G, Berriman, M, Crabtree, J, Aggarwal, G, Caler, E, Renauld, H, Worthey, E, Hertz-Fowler, C, Ghedi, E, Peacock, C, Bartholomeu, D, Haas, B, Tran, A, Wortman, J, Alsmark, Ucm, Angiuoli, S, Anupama, A, Badger, J, Bringaud, F, Cadag, E, Carlton, J, Cerqueira, G, Creasy, T, Delcher, A, Djikeng, A, Embley, T, Hauser, C, Ivens, A, Kummerfeld, S, Pereira-Leal, J, Nilsson, D, Peterson, J, Salzberg, S, Shallom, J, Silva, J, Sundaram, J, Westenberger, S, White, O, Metville, S, Donelson, J, Andersson, B, Stuart, K and Hall, N (2005) Comparative genomics of trypanosomatid parasitic protozoa. Science 309, 404–409.CrossRefGoogle ScholarPubMed
Feitosa, LM, da Silva, ER, Hoelz, LVB, Souza, DL, Come, JAASS, Cardoso-Santos, C, Batista, MM, Soeiro, MNC, Boechat, N and Pinheiro, LCS (2019) New pyrazolopyrimidine derivatives as Leishmania amazonensis arginase inhibitors. Bioorganic & Medical Chemistry 27, 3061–3069.CrossRefGoogle ScholarPubMed
Harder, E, Damm, W, Maple, J, Wu, C, Reboul, M, Xiang, JY, Wang, L, Lupyan, D, Dahlgren, MK, Knight, JL, Kaus, JW, Cerutti, DS, Krilov, G, Jorgensen, WL, Abel, R and Friesner, RA (2016) OPLS3: a force field providing broad coverage of drug-like small molecules and proteins. Journal of Chemical Theory and Computation 12, 281–296.CrossRefGoogle ScholarPubMed
Katsuno, K, Burrows, JN, Duncan, K, van Huijsduijnen, RH and Kaneko, T (2015) Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nature Reviews Drug Discovery 14, 751–758.CrossRefGoogle ScholarPubMed
Khare, S, Nagle, AS, Biggart, A, Lai, YH, Liang, F, Davis, LC, Barnesn, SW, Mathison, CJN, Myburgh, E, Gao, MY, Gillespie, JR, Liu, X, Tan, JL, Stinson, M, Rivera, IC, Ballard, J, Yeh, V, Groessl, T, Federe, G, Koh, HXY, Venable, JD, Bursulaya, B, Shapiro, M, Mishra, PK, Spraggon, G, Brock, A, Mottram, JC, Buckner, FS, Rao, SPS, Wen, BG, Walker, JR, Tuntland, T, Molteni, V, Glynne, RJ and Supek, F (2016) Proteasome inhibition for treatment of Leishmaniasis, Chagas disease and sleeping sickness. Nature 537, 229–233.CrossRefGoogle ScholarPubMed
Kumar, A and Zhang, KYJ (2018) Advances in the development of shape similarity methods and their application in drug discovery. Frontiers in Chemistry 6, 315.CrossRefGoogle ScholarPubMed
Lombardo, F, Desai, PV, Arimoto, R, Desino, KE, Fischer, H, Keefer, CE, Petersson, C, Winiwarter, S and Broccatelli, F (2017) In silico absorption, distribution, metabolism, excretion, and pharmacokinetics (ADME-PK): utility and best practices. An industry perspective from the international consortium for innovation through quality in pharmaceutical development. Journal of Medical Chemistry 60, 9097–9113.CrossRefGoogle ScholarPubMed
Martins, AL, Barreto, JA, Lauris, JR and Martins, AC (2014) American tegumentary leishmaniasis: correlations among immunological, histopathological and clinical parameters. Anais Brasileiros de Dermatologia 89, 52–58.CrossRefGoogle ScholarPubMed
Mikus, J and Sterverding, D (2000) A simple colorimetric to screen drug cytotoxicity against Leishmania using the dye Alamar blue. Parasitology international 48, 265–269.CrossRefGoogle ScholarPubMed
Okwor, I and Uzonna, J (2016) Social and economic burden of human leishmaniasis. American Journal of Tropical Medical Hygiene 94, 489–493.CrossRefGoogle ScholarPubMed
QikProp (2017) Virtual screening workflow, Schrödinger Release 2017-2: Maestro, Schrödinger, LLC, New York, NY.Google Scholar
Romanha, AJ, Castro, SL, Soeiro Mde, N, Lannes-Vieira, J, Ribeiro, I, Talvani, A, Bourdin, B, Blum, B, Olivieri, B, Zani, C, Spadafora, C, Chiari, E, Chatelain, E, Chaves, G, Calzada, JE, Bustamante, JM, Freitas-Junior, LH, Romero, LI, Bahia, MT, Lotrowska, M, Soares, M, Andrade, SG, Armstrong, T, Degrave, W and Andrade Zde, A (2010) In vitro and in vivo experimental models for drug screening and development for Chagas disease. Memórias do Instituto Oswaldo Cruz 105, 233–238.CrossRefGoogle ScholarPubMed
Ruoti, M, Oddone, R, Lampert, N, Orué, E, Miles, MA, Alexander, N, Rehman, AM, Njord, R, Shu, S, Brice, S, Sinclair, B and Krentel, A (2013) Mucocutaneous leishmaniasis: knowledge, attitudes, and practices among Paraguayan communities, patients, and health professionals. Journal of Tropical Medicine 2013, 538629. https://doi.org/10.1155/2013/538629CrossRefGoogle ScholarPubMed
Santos, CC, Lionel, JR, Peres, RB, Batista, MM, da Silva, PB, de Oliveira, GM, da Silva, CF, Batista, D, Souza, S, Andrade, CH, Neves, BJ, Braga, RC, Patrick, DA, Bakunova, SM, Tidwell, RR and Soeiro, M (2018) In vitro, in silico, and in vivo analyses of novel aromatic amidines against Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy, 62: e02205–17.Google ScholarPubMed
Stacey, G (2006) Primary cell cultures and immortal cell lines. Encyclopedia of Life Sciences. doi:10.1038/npg.els.0003960.CrossRefGoogle Scholar
Swinney, DC and Anthony, J (2011) How were new medicines discovered? Nature Reviews Drug Discovery 10, 507–519.CrossRefGoogle ScholarPubMed
Van Bocxlaer, K, Caridha, D, Black, C, Vesely, B, Leed, S, Sciotti, RJ, Wijnant, GJ, Yardley, V, Braillard, S, Mowbray, CE, Ioset, JR and Croft, SL (2019) Novel benzoxaborole, nitroimidazole and aminopyrazoles with activity against experimental cutaneous leishmaniasis. International Journal for Parasitology: Drugs and Drug Resistance 11, 129–138. doi: 10.1016/j.ijpddr.2019.02.002Google ScholarPubMed
Walker, DM, Oghumu, S, Gupta, G, McGwire, BS, Drew, ME and Satoskar, AR (2014) Mechanisms of cellular invasion by intracellular parasites. Cellular and Molecular Life Sciences 71, 1245–1263.CrossRefGoogle ScholarPubMed
World Health Organization (2020) Leishmaniasis factsheet – 2015 (last update 2 March 2020) Brazil. Available at https://www.who.int/en/news-room/fact-sheets/detail/leishmaniasis (Accessed 8 March 2020).Google Scholar