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Previously, through collective efforts of chemoinformaticians and chemists, the group has created two libraries: the essential eIMS containing 578 in\u2010stock 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\u2010groups. In this article, validation of this library design approach is aimed, which is built on scaffold\u2010based structuring and decoration guided by chemists\u2019 expertise. Specifically, its effectiveness is evaluated in comparison to the widely adopted reaction\u2010 and building block\u2010based approach. Using Enamine REAL Space library, two scaffold\u2010focused datasets are developed and the make\u2010on\u2010demand 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\u2010groups are not identified as such in the make\u2010on\u2010demand library. Synthetic accessibility analysis of the compound sets indicated overall low to moderate synthetic difficulty. These findings confirm the value of the scaffold\u2010based method for generating focused libraries, offering high potential for lead optimization in drug discovery.<\/jats:p>","DOI":"10.1002\/cmdc.202500518","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T20:55:52Z","timestamp":1763153752000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Scaffold\u2010Based Libraries Versus Make\u2010on\u2010Demand Space: A Comparative Assessment of Chemical Content"],"prefix":"10.1002","volume":"20","author":[{"given":"L\u00e9onard","family":"Bui","sequence":"first","affiliation":[{"name":"Laboratoire d\u2019Innovation Th\u00e9rapeutique UMR 7200 University of Strasbourg, Faculty of Pharmacy  74 route du Rhin 67400 Illkirch\u2010Graffenstaden 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