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      The Open Access Malaria Box: A Drug Discovery Catalyst for Neglected Diseases

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          Abstract

          Historically, one of the key problems in neglected disease drug discovery has been identifying new and interesting chemotypes. Phenotypic screening of the malaria parasite, Plasmodium falciparum has yielded almost 30,000 submicromolar hits in recent years. To make this collection more accessible, a collection of 400 chemotypes has been assembled, termed the Malaria Box. Half of these compounds were selected based on their drug-like properties and the others as molecular probes. These can now be requested as a pharmacological test set by malaria biologists, but importantly by groups working on related parasites, as part of a program to make both data and compounds readily available. In this paper, the analysis and selection methodology and characteristics of the compounds are described.

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          Most cited references15

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          Privileged scaffolds for library design and drug discovery.

          This review explores the concept of using privileged scaffolds to identify biologically active compounds through building chemical libraries. We hope to accomplish three main objectives: to provide one of the most comprehensive listings of privileged scaffolds; to reveal through four selected examples the present state of the art in privileged scaffold library synthesis (in hopes of inspiring new and even more creative approaches); and also to offer some thoughts on how new privileged scaffolds might be identified and exploited. Copyright 2010 Elsevier Ltd. All rights reserved.
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            Chemical genetics of Plasmodium falciparum

            Malaria caused by Plasmodium falciparum is a catastrophic disease worldwide (880,000 deaths yearly). Vaccine development has proved difficult and resistance has emerged for most antimalarials. In order to discover new antimalarial chemotypes, we have employed a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library, many of which exhibited potent in vitro activity against drug resistant strains, and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in multiple organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Overall, our findings provide the scientific community with new starting points for malaria drug discovery.
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              Targeting the hypnozoite reservoir of Plasmodium vivax: the hidden obstacle to malaria elimination.

              Plasmodium vivax is the major species of malaria parasite outside Africa. It is especially problematic in that the infection can relapse in the absence of mosquitoes by activation of dormant hypnozoites in the liver. Medicines that target the erythrocytic stages of Plasmodium falciparum are also active against P. vivax, except where these have been compromised by resistance. However, the only clinical therapy against relapse of vivax malaria is the 8-aminoquinoline, primaquine. This molecule has the drawback of causing haemolysis in genetically sensitive patients and requires 14 days of treatment. New, safer and more-easily administered drugs are urgently needed, and this is a crucial gap in the broader malaria-elimination agenda. New developments in cell biology are starting to open ways to the next generation of drugs against hypnozoites. This search is urgent, given the time needed to develop a new medication. Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                17 June 2013
                : 8
                : 6
                : e62906
                Affiliations
                [1 ]Medicines for Malaria Venture (MMV), Geneva, Switzerland
                [2 ]SCYNEXIS Inc., Research Triangle Park, North Carolina, United States of America
                National University of Singapore, Singapore
                Author notes

                Competing Interests: PK is employed by SCYNEXIS, Inc. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: TS JNB PK SMD TNCW PW. Performed the experiments: TS PK SMD PW. Analyzed the data: TS JNB PK PW. Wrote the paper: TS JNB PK TNCW PW.

                Article
                PONE-D-13-06085
                10.1371/journal.pone.0062906
                3684613
                23798988
                9244e551-6877-4109-ad42-fdad8661a331
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 4 February 2013
                : 21 March 2013
                Page count
                Pages: 8
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Biology
                Microbiology
                Protozoology
                Parastic Protozoans
                Plasmodium Falciparum
                Parasitology
                Chemistry
                Chemical Biology
                Computational Chemistry
                Medicinal Chemistry
                Organic Chemistry
                Medicine
                Drugs and Devices
                Drug Research and Development
                Drug Discovery
                Infectious Diseases
                Parasitic Diseases
                Malaria
                Plasmodium Falciparum
                Tropical Diseases (Non-Neglected)
                Malaria
                Plasmodium Falciparum

                Uncategorized
                Uncategorized

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