Chemical libraries are essential in drug discovery, providing a vast variety of compounds for screening and exploration. Previously, through collective efforts of chemoinformaticians and chemists, the group has created two libraries: the essential eIMS containing 578 in-stock compounds on plates ready for high throughput screening and a companion virtual library vIMS, containing 821.069 compounds derived from the scaffolds of the eIMS compounds, and decorated with substituents from customized collection of R-groups. In this article, validation of this library design approach is aimed, which is built on scaffold-based structuring and decoration guided by chemists' expertise. Specifically, its effectiveness is evaluated in comparison to the widely adopted reaction- and building block-based approach. Using Enamine REAL Space library, two scaffold-focused datasets are developed and the make-on-demand chemical space containing the same scaffolds are systematically compared. The results showed similarity between the two, but with limited strict overlap. Interestingly, a significant portion of the R-groups are not identified as such in the make-on-demand library. Synthetic accessibility analysis of the compound sets indicated overall low to moderate synthetic difficulty. These findings confirm the value of the scaffold-based method for generating focused libraries, offering high potential for lead optimization in drug discovery.
Keywords: chemical space; cheminformatics; enumeration; library design; library diversity.
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