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In silico repositioning of approved drugs for rare and neglected diseases. Drug Discov Today

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Drug discovery today (Impact Factor: 5.96). 03/2011; 16(7-8):298-310. DOI: 10.1016/j.drudis.2011.02.016
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ABSTRACT One approach to speed up drug discovery is to examine new uses for existing approved drugs, so-called 'drug repositioning' or 'drug repurposing', which has become increasingly popular in recent years. Analysis of the literature reveals many examples of US Food and Drug Administration-approved drugs that are active against multiple targets (also termed promiscuity) that can also be used to therapeutic advantage for repositioning for other neglected and rare diseases. Using proof-of-principle examples, we suggest here that with current in silico technologies and databases of the structures and biological activities of chemical compounds (drugs) and related data, as well as close integration with in vitro screening data, improved opportunities for drug repurposing will emerge for neglected or rare/orphan diseases.

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Available from: Antony John Williams, Aug 19, 2015
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    • "The previous discussion explains why drug repositioning constitutes a key strategy in the field of drug discovery and development for orphan diseases, where there is an obvious need of collaborative public-private partnerships [20] [22] [90] [91]. Several initiatives such as WHO Special Programme for Research and Training in Tropical Disease, the Medicines for Malaria Venture, the Global Alliance for TB Drug Development, Drugs for Neglected Diseases and the Open Source Drug Discovery initiative have recognized drug repositioning as an attractive option to provide low-cost access to medications in developing countries [92]. "
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    ABSTRACT: Drug repurposing/reprofiling has attracted considerable attention during the last decade. The object of such approach is to discover second or further medical uses of known chemicals, i. e. targeting existing, withdrawn or abandoned drugs, or yet to be pursued clinical candidates to new disease areas. Recently (2011-2012), the US and UK governments launched public-private joint initiatives towards finding new uses of previously shelved compounds (drug rescue). While in the past repurposing emerged from serendipitous findings and/or from rational exploitation of drug side-effects (e.g. sildenafil, aspirin), the current tendency in the drug development field focuses on knowledge-based drug repurposing, particularly, computer-aided repositioning approaches. The present chapter reviews different cheminformatic and bioinformatic applications, as well as high-throughput literature analysis, oriented to the discovery of new medical uses of known drugs. Applications of such strategies to the discovery of innovative medications for neglected or rare diseases are discussed. Finally, we also review publicly available resources (e.g. chemical libraries) valuable for reprofiling.
    Frontiers in Computational Chemistry (Vol. 1), Edited by Zaheer-ul-Haq, J. D. Madura, 01/2015: chapter 2: pages 44-81; Bentham Science., ISBN: 978-1-60805-865-5
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    • "Therefore, antiparasitic drugs that inhibit vital redox reactions or promote oxidative stress in parasites may be promising candidates (Pal and Bandyopadhyay, 2012). Drug repurposing has been a strategic, efficient and costeffective approach for finding novel and effective antiparasitics for neglected diseases (Ekins et al., 2011). Nitazoxanide (NTZ) is a synthetic nitrothiazolyl-salicylamide derivative that is approved for treating infectious diarrhoea caused by Cryptosporidium parvum and Giardia lamblia, as well as others parasites such as Giardia intestinalis, Entamoeba histolytica, and Trichomonas vaginalis (Anderson and Curran, 2007). "
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    ABSTRACT: Studying the cellular death pathways in Leishmania is an important aspect of discovering new antileshmanials. While using a drug repositioning approach, the lethal action of the nitrothiazolyl-salicylamide derivative nitazoxanide (NTZ) was investigated against Leishmania (L.) infantum. The in vitro antileishmanial activity and cytotoxicity were assessed using both parasite stages and mammalian NCTC cells, respectively. The lethal action of NTZ was investigated by detecting the phosphatidylserine (PS) exposure, reactive oxygen species (ROS) regulation, plasma membrane permeability, mitochondrial membrane potential and ultrastructural modifications by transmission electron microscopy. NTZ's activity against L. infantum was confirmed, producing IC50 values of 42.71μg/mL against promastigotes and 6.78μg/mL against intracellular amastigotes. NTZ rapidly altered the cellular metabolism of promastigotes by depolarising the mitochondrial membrane and up-regulating the reactive oxygen species (ROS). In addition, the flow cytometry data revealed an intense and time-dependent exposure of PS in promastigotes. When using SYTOX® Green as a fluorescent probe, NTZ demonstrated no interference in plasma membrane permeability. The ultrastructural alterations in promastigotes were time-dependent and caused chromatin condensation, plasma membrane blebbing and mitochondrial swelling. These data suggest that NTZ induced oxidative stress in Leishmania (L.) infantum and might be a useful compound for investigating new therapeutic targets.
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    ABSTRACT: Despite affecting around 8 million people worldwide and representing an economic burden above $7 billion/ year, currently approved medications to treat Chagas disease are still limited to two drugs, nifurtimox and benznidazole, which were developed more than 40 years ago and present important efficacy and safety limitations. Drug repositioning (i.e. finding second or further therapeutic indications for known drugs) has raised considerable interest within the international drug development community. There are many explanations to the current interest on drug repositioning including the possibility to partially circumvent clinical trials and the consequent saving in time and resources. It has been suggested as a particular attractive approach for the development of novel therapeutics for neglected diseases, which are usually driven by public or non-profit organizations. Here we review current computer-guided approaches to drug repositioning and reports on drug repositioning stories oriented to Chagas disease, with a focus on computer-guided drug repositioning campaigns.
    Mini Reviews in Medicinal Chemistry 03/2015; 15(3):182-193. DOI:10.2174/138955751503150312120208 · 3.19 Impact Factor
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