PLoS pathogens · 2016

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

СтатьяПоддержка правительства СШАПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди

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Van Voorhis Wesley C, Adams John H, Adelfio Roberto, Ahyong Vida, Akabas Myles H, Alano Pietro, Alday Aintzane, Alemán Resto Yesmalie, Alsibaee Aishah, Alzualde Ainhoa, Andrews Katherine T, Avery Simon V, Avery Vicky M, Ayong Lawrence, Baker Mark, Baker Stephen, Ben Mamoun Choukri, Bhatia Sangeeta, Bickle Quentin, Bounaadja Lotfi, Bowling Tana, Bosch Jürgen, Boucher Lauren E, Boyom Fabrice F, Brea Jose, Brennan Marian, Burton Audrey, Caffrey Conor R, Camarda Grazia, Carrasquilla Manuela, Carter Dee, Belen Cassera Maria, Chih-Chien Cheng Ken, Chindaudomsate Worathad, Chubb Anthony, Colon Beatrice L, Colón-López Daisy D, Corbett Yolanda, Crowther Gregory J, Cowan Noemi, D'Alessandro Sarah, Le Dang Na, Delves Michael, DeRisi Joseph L, Du Alan Y, Duffy Sandra, Abd El-Salam El-Sayed Shimaa, Ferdig Michael T, Fernández Robledo José A, Fidock David A, Florent Isabelle, Fokou Patrick V T, Galstian Ani, Gamo Francisco Javier, Gokool Suzanne, Gold Ben, Golub Todd, Goldgof Gregory M, Guha Rajarshi, Guiguemde W Armand, Gural Nil, Guy R Kiplin, Hansen Michael A E, Hanson Kirsten K, Hemphill Andrew, Hooft van Huijsduijnen Rob, Horii Takaaki, Horrocks Paul, Hughes Tyler B, Huston Christopher, Igarashi Ikuo, Ingram-Sieber Katrin, Itoe Maurice A, Jadhav Ajit, Naranuntarat Jensen Amornrat, Jensen Laran T, Jiang Rays H Y, Kaiser Annette, Keiser Jennifer, Ketas Thomas, Kicka Sebastien, Kim Sunyoung, Kirk Kiaran, Kumar Vidya P, Kyle Dennis E, Lafuente Maria Jose, Landfear Scott, Lee Nathan, Lee Sukjun, Lehane Adele M, Li Fengwu, Little David, Liu Liqiong, Llinás Manuel, Loza Maria I, Lubar Aristea, Lucantoni Leonardo, Lucet Isabelle, Maes Louis, Mancama Dalu, Mansour Nuha R, March Sandra, McGowan Sheena, Medina Vera Iset, Meister Stephan, Mercer Luke, Mestres Jordi, Mfopa Alvine N, Misra Raj N, Moon Seunghyun, Moore John P, Morais Rodrigues da Costa Francielly, Müller Joachim, Muriana Arantza, Nakazawa Hewitt Stephen, Nare Bakela, Nathan Carl, Narraidoo Nathalie, Nawaratna Sujeevi, Ojo Kayode K, Ortiz Diana, Panic Gordana, Papadatos George, Parapini Silvia, Patra Kailash, Pham Ngoc, Prats Sarah, Plouffe David M, Poulsen Sally-Ann, Pradhan Anupam, Quevedo Celia, Quinn Ronald J, Rice Christopher A, Abdo Rizk Mohamed, Ruecker Andrea, St Onge Robert, Salgado Ferreira Rafaela, Samra Jasmeet, Robinett Natalie G, Schlecht Ulrich, Schmitt Marjorie, Silva Villela Filipe, Silvestrini Francesco, Sinden Robert, Smith Dennis A, Soldati Thierry, Spitzmüller Andreas, Stamm Serge Maximilian, Sullivan David J, Sullivan William, Suresh Sundari, Suzuki Brian M, Suzuki Yo, Swamidass S Joshua, Taramelli Donatella, Tchokouaha Lauve R Y, Theron Anjo, Thomas David, Tonissen Kathryn F, Townson Simon, Tripathi Abhai K, Trofimov Valentin, Udenze Kenneth O, Ullah Imran, Vallieres Cindy, Vigil Edgar, Vinetz Joseph M, Voong Vinh Phat, Vu Hoan, Watanabe Nao-Aki, Weatherby Kate, White Pamela M, Wilks Andrew F, Winzeler Elizabeth A, Wojcik Edward, Wree Melanie, Wu Wesley, Yokoyama Naoaki, Zollo Paul H A, Abla Nada, Blasco Benjamin, Burrows Jeremy, Laleu Benoît, Leroy Didier, Spangenberg Thomas, Wells Timothy, Willis Paul A

Аннотация

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.

Предметные рубрики MeSH

Antimalarials Datasets as Topic Drug Discovery Drug Evaluation, Preclinical Humans Malaria Neglected Diseases Small Molecule Libraries

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

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH