Design of the Global Health chemical diversity library v2 for screening against infectious diseases.

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). Author summary: Screening of diverse compound libraries is a powerful way to find chemical start points for drug discovery programmes. There is a lack of such chemical libraries available for neglected infectious diseases and other neglected areas such as non-hormonal contraception. In this paper we describe the design of such a library of 30,000 compounds (graphical abstract). The aim was to develop a library of diverse chemical matter unlikely to have been screened in these disease areas. The compounds were selected from the REAL (REadily AccessibLe) Enamine library, a virtual library of 4.5 billion compounds. The methodology for selection of the compounds is described, along with a detailed analysis of the physicochemical properties of the compounds and comparison to other libraries that we have assembled. This shows that the library contains hit/lead-like compounds suitable as chemical start points, and whilst it covers a similar space to some other libraries, the material within the library is mainly different to other libraries. Copies of the library will be made available for screening; the process for gaining access to this library is described. [ABSTRACT FROM AUTHOR]