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

Collaborations in Chemistry, 601 Runnymede Avenue, Jenkintown, PA 19046, USA.
Drug discovery today (Impact Factor: 6.69). 03/2011; 16(7-8):298-310. DOI: 10.1016/j.drudis.2011.02.016
Source: PubMed


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
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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The object of such approach is to discover second or further medical uses of known chemicals, i. e. targeting existing, withdrawn or abandoned drugs, or yet to be pursued clinical candidates to new disease areas.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.
    Full-text · Chapter · Jan 2015
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    • "Reliance on the traditional drug development pathways to deliver on this goal would have significant implications on both cost and time. Drug repositioning or the screening of existing drugs for new uses, affords an attractive, alternate and valid paradigm for drug discovery [7,8]. Recent successes like the repositioning of Viagra® for erectile dysfunction and Thalidomide® for Erythema nodosum leprosum, have lead drug companies to explore repositioning on a more systematic basis [9,10]. "
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    ABSTRACT: Drug repurposing or repositioning refers to the usage of existing drugs in diseases other than those it was originally used for. For diseases like malaria, where there is an urgent need for active drug candidates, the strategy offers a route to significantly shorten the traditional drug development pipelines. Preliminary high-throughput screens on patent expired drug libraries have recently been carried out for Plasmodium falciparum. This study reports the systematic and objective further interrogation of selected compounds reported in these studies, to enable their repositioning as novel stand-alone anti-malarials or as combinatorial partners. SYBR Green flow cytometry and micro-titre plate assays optimized in the laboratory were used to monitor drug susceptibility of in vitro cultures of P. falciparum K1 parasite strains. Previously described fixed-ratio methods were adopted to investigate drug interactions. Emetine dihydrochloride hydrate, an anti-protozoal drug previously used for intestinal and tissue amoebiasis was shown to have potent inhibitory properties (IC50 doses of ~ 47nM) in the multidrug resistant K1 strain of P. falciparum. The sum 50% fractional inhibitory concentration ([n-ary summation]FIC50, 90) of the interaction of emetine dihydrochloride hydrate and dihydroartemisinin against the KI strains of P. falciparum ranged from 0.88-1.48. The results warrant further investigation of emetine dihydrochloride hydrate as a potential stand-alone anti-malarial option. The interaction between the drug and the current front line dihydroartemisinin ranged from additive to mildly antagonistic in the fixed drug ratios tested.
    Full-text · Article · Oct 2013 · Malaria Journal
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    • "So far, these discoveries have mostly been achieved serendipitously through the clinical monitoring of drug effects. However, in recent years, the availability of huge information on the genetic basis of human disorders, on gene regulation, on protein structure and on drug-target interactions has generated unprecedented opportunities to pursue drug repositioning on a more rational ground [8]. Accordingly, several computational approaches have been developed to discover unrecognized or non-explicit connections between drugs, targets and diseases. "
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    ABSTRACT: The development of new therapies for orphan genetic diseases represents an extremely important medical and social challenge. Drug repositioning, i.e. finding new indications for approved drugs, could be one of the most cost- and time-effective strategies to cope with this problem, at least in a subset of cases. Therefore, many computational approaches based on the analysis of high throughput gene expression data have so far been proposed to reposition available drugs. However, most of these methods require gene expression profiles directly relevant to the pathologic conditions under study, such as those obtained from patient cells and/or from suitable experimental models. In this work we have developed a new approach for drug repositioning, based on identifying known drug targets showing conserved anti-correlated expression profiles with human disease genes, which is completely independent from the availability of 'ad hoc' gene expression data-sets. By analyzing available data, we provide evidence that the genes displaying conserved anti-correlation with drug targets are antagonistically modulated in their expression by treatment with the relevant drugs. We then identified clusters of genes associated to similar phenotypes and showing conserved anticorrelation with drug targets. On this basis, we generated a list of potential candidate drug-disease associations. Importantly, we show that some of the proposed associations are already supported by independent experimental evidence. Our results support the hypothesis that the identification of gene clusters showing conserved anticorrelation with drug targets can be an effective method for drug repositioning and provide a wide list of new potential drug-disease associations for experimental validation.
    Full-text · Article · Oct 2013 · BMC Bioinformatics
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