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      Identification of Levothyroxine Antichagasic Activity through Computer-Aided Drug Repurposing

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          Abstract

          Cruzipain (Cz) is the major cysteine protease of the protozoan Trypanosoma cruzi, etiological agent of Chagas disease. A conformation-independent classifier capable of identifying Cz inhibitors was derived from a 163-compound dataset and later applied in a virtual screening campaign on the DrugBank database, which compiles FDA-approved and investigational drugs. 54 approved drugs were selected as candidates, 3 of which were acquired and tested on Cz and T. cruzi epimastigotes proliferation. Among them, levothyroxine, traditionally used in hormone replacement therapy in patients with hypothyroidism, showed dose-dependent inhibition of Cz and antiproliferative activity on the parasite.

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          Most cited references47

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          Virtual screening workflow development guided by the "receiver operating characteristic" curve approach. Application to high-throughput docking on metabotropic glutamate receptor subtype 4.

          The "receiver operating characteristic" (ROC) curve method is a well-recognized metric used as an objective way to evaluate the ability of a given test to discriminate between two populations. This facilitates decision-making in a plethora of fields in which a wrong judgment may have serious consequences including clinical diagnosis, public safety, travel security, and economic strategies. When virtual screening is used to speed-up the drug discovery process in pharmaceutical research, taking the right decision upon selecting or discarding a molecule prior to in vitro evaluation is of paramount importance. Characterizing both the ability of a virtual screening workflow to select active molecules and the ability to discard inactive ones, the ROC curve approach is well suited for this critical decision gate. As a case study, the first virtual screening workflow focused on metabotropic glutamate receptor subtype 4 (mGlu4R) agonists is reported here. Six compounds out of 38 selected and tested in vitro were shown to have agonist activity on this target of therapeutic interest.
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            Specific chemotherapy of Chagas disease: controversies and advances.

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              Current epidemiological trends for Chagas disease in Latin America and future challenges in epidemiology, surveillance and health policy.

              Chagas disease, named after Carlos Chagas, who first described it in 1909, exists only on the American Continent. It is caused by a parasite, Trypanosoma cruzi, which is transmitted to humans by blood-sucking triatomine bugs and via blood transfusion. Chagas disease has two successive phases: acute and chronic. The acute phase lasts six-eight weeks. Several years after entering the chronic phase, 20-35% of infected individuals, depending on the geographical area, will develop irreversible lesions of the autonomous nervous system in the heart, oesophagus and colon, and of the peripheral nervous system. Data on the prevalence and distribution of Chagas disease improved in quality during the 1980s as a result of the demographically representative cross-sectional studies in countries where accurate information was not previously available. A group of experts met in Brasilia in 1979 and devised standard protocols to carry out countrywide prevalence studies on human T. cruzi infection and triatomine house infestation. Thanks to a coordinated multi-country programme in the Southern Cone countries, the transmission of Chagas disease by vectors and via blood transfusion was interrupted in Uruguay in 1997, in Chile in 1999 and in Brazil in 2006; thus, the incidence of new infections by T. cruzi across the South American continent has decreased by 70%. Similar multi-country initiatives have been launched in the Andean countries and in Central America and rapid progress has been reported towards the goal of interrupting the transmission of Chagas disease, as requested by a 1998 Resolution of the World Health Assembly. The cost-benefit analysis of investment in the vector control programme in Brazil indicates that there are savings of US$17 in medical care and disabilities for each dollar spent on prevention, showing that the programme is a health investment with very high return. Many well-known research institutions in Latin America were key elements of a worldwide network of laboratories that carried out basic and applied research supporting the planning and evaluation of national Chagas disease control programmes. The present article reviews the current epidemiological trends for Chagas disease in Latin America and the future challenges in terms of epidemiology, surveillance and health policy.
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                Author and article information

                Journal
                ScientificWorldJournal
                ScientificWorldJournal
                TSWJ
                The Scientific World Journal
                Hindawi Publishing Corporation
                1537-744X
                2014
                30 January 2014
                : 2014
                : 279618
                Affiliations
                1Medicinal Chemistry, Department of Biological Sciences, Faculty of Exact Sciences, National University of La Plata, 47 y 115, La Plata (B1900AJI) Buenos Aires, Argentina
                2Instituto de Ciencia y Tecnología Dr. César Milstein (ICT Milstein), Argentinean National Council of Scientific and Technical Research (CONICET), Saladillo 2468, Ciudad Autónoma de Buenos Aires (C1440FFX), Argentina
                3Instituto de Investigaciones Bioquímicas de Buenos Aires, Argentinean National Council of Scientific and Technical Research (CONICET), Avenida Patricias Argentinas 435, Ciudad Autónoma de Buenos Aires (C1405BWE), Argentina
                Author notes

                Academic Editors: C. Mackereth, A. Paiardini, and X. Qiu

                Author information
                http://orcid.org/0000-0003-3178-826X
                Article
                10.1155/2014/279618
                3926237
                24592161
                a0095713-bcaa-40a7-9c9a-2fd3620357cf
                Copyright © 2014 Carolina L. Bellera et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 August 2013
                : 13 November 2013
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