Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond.

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Van Voorhis, Wesley C.ca
• dc.contributor.author Mestres i López, Jordica
• dc.contributor.author Spitzmüller, Andreasca
• dc.contributor.author Willis, Paul A.ca
• dc.date.accessioned 2016-11-29T10:57:02Z
• dc.date.available 2016-11-29T10:57:02Z
• dc.date.issued 2016
• dc.description.abstract A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.ca
• dc.description.sponsorship Thanks to the UK DFID and the Bill and Melinda Gates Foundation Grand Challenges Explorations for providing funding for testing of the Malaria Box and funding the support of individual groups including: Medicines for Malaria Venture MMV Challenge Grant, Grant Numbers MMV 12/0048 and MMV 12/0076 (to JHA), the Australian Research Council (FT10100185 to SAP; FT0991213 to KTA and LP120200557 awarded to VMA), Bill & Melinda Gates Foundation Grant OPP1040394 to PA, OPP1040399 to DAF and VMA and OPP1086189 to KKH, OPP1069393 and OPP1119049 to ML, OPP1024029 to CN, the Bloomberg Family Foundation (JBr), JHMRI for a predoctoral fellowship, the US NIH for the CBI training grant T32GM080189 (to LEB), R01GM104486 (to PAW & WS), R01AI117017 (to JHA) the National Science Foundation Graduate Research Fellowship Program Grant No.DGE-1232825 (DDCL), the South African Medical Research Council Strategic Health Innovation Partnerships (grant V6YBT51 to DM) and the Council for Scientific and Industrial Research (grant V1YTB95, to DM), and the French ANR program Mammamia (ANR-12-BS07-0020-01).
• dc.format.mimetype application/pdfca
• dc.identifier.citation Van Voorhis WC, Adams JH, Adelfio R, Ahyong V, Akabas MH, Alano P. et al Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond. PLoS Pathog. 2016 Jul 28;12(7):e1005763. doi: 10.1371/journal.ppat.1005763ca
• dc.identifier.doi http://dx.doi.org/10.1371/journal.ppat.1005763
• dc.identifier.issn 1553-7366
• dc.identifier.uri http://hdl.handle.net/10230/27627
• dc.language.iso engca
• dc.publisher Public Library of Science (PLoS) ca
• dc.relation.ispartof PLOS Pathogens. 2016 Jul 28;12(7):e1005763
• dc.rights This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.ca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.rights.uri https://creativecommons.org/publicdomain/zero/1.0/ca
• dc.subject.other Medicamentsca
• dc.subject.other Malària -- Medicamentsca
• dc.title Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond.ca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/publishedVersionca