The structures of the original GHCDL.

There is a need for novel chemical matter for phenotypic and target-based screens to find starting points for drug discovery programmes in neglected infectious diseases and non-hormonal contraceptives that disproportionately affect Low- and Middle-Income Countries (LMICs). In some disease areas multiple screens of corporate and other libraries have been carried out, giving rise to some valuable starting points and leading to preclinical candidates. Whilst in other disease areas, little screening has been carried out. Much screening against pathogens has been conducted phenotypically as there are few robustly validated protein targets. However, many of the active compound series identified share the same molecular targets. To address the need for new chemical material, in this article we describe the design of a new library, designed for screening in drug discovery programmes for neglected infectious diseases. The compounds have been selected from the Enamine REAL (REadily AccessibLe) library, a virtual library which contains approximately 4.5 billion molecules. The molecules theoretically can be synthesized quickly using commercially available intermediates and building blocks. The vast majority of these have not been prepared before, so this is a source of novel compounds. In this paper we describe the design of a diverse library of 30,000 compounds from this collection (graphical abstract). The new library will be made available to laboratories working in neglected infectious diseases, subject to a review process. The project has been supported by the Bill & Melinda Gates Foundation and the Wellcome Trust (Wellcome).

针对被忽视的传染病，以及主要影响中低收入国家（Low- and Middle-Income Countries, LMICs）的非激素避孕药领域的药物发现项目，亟需可用于表型筛选与基于靶点筛选的新型化学实体，以获取药物开发的起始位点。在部分疾病领域，科研人员已针对企业及其他类型的化合物库开展多轮筛选，获得了若干具有研究价值的起始化合物，并催生了临床前候选药物；而在其余部分疾病领域，相关筛选工作仍较为匮乏。由于经过严谨验证的蛋白质靶点较为稀缺，针对病原体的筛选多以表型筛选为主，但已发现的多数活性化合物系列共享同一分子靶点。为满足新型化学实体的需求，本文阐述了一款全新化合物库的设计方案，该库专为被忽视的传染病药物发现项目中的筛选工作打造。该库中的化合物选自Enamine REAL（REadily AccessibLe）虚拟库，这一虚拟库包含约45亿个分子。理论上，这些分子可通过市售中间体与结构砌块快速合成，其中绝大多数此前从未被合成过，因此该库是新型化合物的重要来源。本文中，我们从该集合中选取30000个化合物，构建了一款多样化的化合物库（详见图文摘要）。该全新化合物库将经审核流程后，向从事被忽视传染病研究的实验室开放共享。本项目得到比尔及梅琳达·盖茨基金会与惠康信托基金（Wellcome）的资助。