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

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.

药物发现新起点匮乏的主要原因在于学术界与产业界之间的互动不足。全球生物学资源的大部分集中在大学中，而药物化学的研究重点仍主要在产业界。开源药物发现，通过信息共享，显然是弥合这一差距的第一步。然而，通过扩大物理化合物的开放共享规模，特别是能够加速发现药物发现新起点的方式，界面问题可以得到特别的解决。疟疾药物开发风险投资公司（Medicines for Malaria Venture）的疟疾盒子（Malaria Box）收集了超过400种化合物，这些化合物代表了在针对恶性疟原虫（Plasmodium falciparum）进行药理学和学术图书馆表型筛选中鉴定出的结构家族。在过去两年中，该套件已几乎分发给全球近200个研究小组，唯一的要求是将筛选信息存入公共领域。本文首次报告了针对疟疾盒子进行的236次筛选，并将这些结果与先前发表的55项检测进行了比较，以允许对合并数据集进行荟萃分析。本文所呈现的生化与细胞检测表明，对于135种（34%）在杀灭疟原虫多个生命周期阶段（包括无性血、肝、配子体、配子和昆虫卵囊阶段）中具有活性的化合物，提出了作用机制。此外，许多化合物对其他病原体也表现出活性，在16种原虫、7种蠕虫、9种细菌和分枝杆菌、登革热蚊子媒介以及NCI60人肿瘤细胞系（包含60个人肿瘤细胞系）的检测中显示出活性。所有化合物的毒理学、药代动力学和代谢特性均被收集，以协助选择最有希望的候选药物进行小鼠概念验证实验和药物化学项目。所有这些检测的数据均得到呈现和分析，以展示如何从涉及人类病原体的生化检测的分散专业知识中选出许多指示剂的卓越先导化合物。这些结果揭示了将涉及人类病原体的生化检测的分散专业知识转化为药物发现起点所具有的巨大潜力，通过提供对新型分子家族的开放访问，并强调了通过额外的微小投资来帮助获取和分配化合物，以及共享数据，如何能够催化针对数十种不同指示剂的药物发现。另一个教训是，当不同小组在同一库中运行多个筛选时，结果可以快速整合，以选择后续药物化学努力中最有价值的新起点。