LAUSR

On‐demand combinatorial spaces are shifting paradigms in early drug discovery, by considerably increasing the searchable chemical space to several billions of compounds while securing their synthetic accessibility. We here systematically compared the on‐the‐shelf available drug‐like chemical space (9 million compounds) to three on‐demand ultra‐large (ODUL) combinatorial fragment spaces (REAL, CHEMriya, GalaXi) covering 32 billion of readily accessible molecules. Surprisingly, only one space (REAL) intersects almost entirely the currently available drug‐like space, suggesting that it is the only ODUL widely suitable for in‐stock hit expansion. Of course, expanding a preliminary ODUL hit in the same chemical space is the best possible strategy to rapidly generate structure‐activity relationships. All three spaces remain well suited to early hit finding initiatives since they all provide numerous unique scaffolds that are not described by on‐the shelf collections.