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利用疟疾盒化合物库开展针对被忽视疾病及其他疾病的开源药物研发。

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

作者信息

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

机构信息

Departments of Medicine, Microbiology, and Global Health, Center for Emerging and Re-emerging Infectious Diseases (CERID) University of Washington, Seattle, Washington, United States of America.

Center for Global Health and Infectious Diseases Research, Department of Global Health, University of South Florida, Tampa, Florida, United States of America.

出版信息

PLoS Pathog. 2016 Jul 28;12(7):e1005763. doi: 10.1371/journal.ppat.1005763. eCollection 2016 Jul.

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.

摘要

药物研发新起点匮乏的一个主要原因是学术界与产业界之间缺乏互动。全球生物学领域的大量资源集中在大学,而药物化学的重点仍主要在产业界。开源药物研发,即信息共享,显然是弥合这一差距的第一步。但尤其可以通过扩大实体化合物的开放共享来弥合这一界面,这将加速药物研发新起点的发现。疟疾药物事业组织的疟疾盒是一个包含400多种化合物的集合,这些化合物代表了在制药和学术文库针对恶性疟原虫进行的表型筛选中鉴定出的结构家族。在过去两年里,该化合物集已分发给全球近200个研究小组,唯一的条件是筛选信息要存入公共领域。本文首次报告了针对疟疾盒进行的236次筛选,并将这些结果与之前发表的55次检测进行了比较,采用的格式允许对合并数据集进行荟萃分析。本文呈现的综合生化和细胞检测表明,在杀死疟原虫多个生命周期阶段(包括无性血液、肝脏、配子体、配子和昆虫动合子阶段)具有活性的135种(34%)化合物的作用机制。此外,许多化合物对其他病原体也表现出活性,在针对16种原生动物、7种蠕虫、9种细菌和分枝杆菌物种、登革热蚊媒以及由60种人类肿瘤细胞系组成的NCI60人类癌细胞系面板的检测中出现了命中结果。收集了所有化合物的毒理学、药代动力学和代谢特性,有助于选择最有前景的候选物用于小鼠概念验证实验和药物化学项目。展示并分析了所有这些检测的数据,以表明如何筛选出针对多种适应症的优秀先导化合物。这些结果揭示了通过开放获取新的分子家族,将涉及人类病原体的生物检测中分散的专业知识转化为药物研发起点的巨大潜力,并强调了为帮助获取和分发化合物以及共享数据而进行的少量额外投资如何能够催化针对数十种不同适应症的药物研发。另一个经验是,当不同小组对同一文库进行多次筛选时,可以迅速整合结果,以选择后续药物化学工作中最有价值的起点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9a77/4965013/45d98c32063c/ppat.1005763.g001.jpg

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