Relevance of the Trillion-Sized Chemical Space “eXplore” as a Source for Drug Discovery

• Published in: ACS medicinal chemistry letters Vol. 14; no. 4; pp. 466 - 472
• Main Authors: Neumann, Alexander, Marrison, Lester, Klein, Raphael
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13.04.2023
• Subjects: chemical space; virtual screening; ligand-based drug discovery; molecular similarity; make-on-demand; combinatorial library
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.3c00021

Within the past two decades, virtual combinatorial compound collections, so-called chemical spaces, became an important molecule source for pharmaceutical research all over the world. The emergence of compound vendor chemical spaces with rapidly growing numbers of molecules raises questions about their application suitability and the quality of the content. Here, we examine the composition of the recently published and, so far, biggest chemical space, “eXplore”, which comprises approximately 2.8 trillion virtual product molecules. The utility of eXplore to retrieve interesting chemistry around approved drugs and common Bemis Murcko scaffolds has been assessed with several methods (FTrees, SpaceLight, SpaceMACS). Further, the overlap between several vendor chemical spaces and a physicochemical property distribution analysis has been performed. Despite the straightforward chemical reactions underlying its setup, eXplore is demonstrated to provide relevant and, most importantly, easily accessible molecules for drug discovery campaigns.