Abstract
<jats:p>Ultra-large virtual libraries have become a cornerstone of modern early-stage drug discovery, enabling the rapid exploration of billions of compounds. The chemical space accessible to most screening campaigns, while sufficiently diverse to generate hits for many protein targets, remains constrained by commercially available building blocks and a set of well-established synthetic reactions. To address this limitation, we present the continued development of the Pan-Canadian Chemical Library (PCCL), a communitydriven effort to expand the accessible chemical space beyond commercial libraries by incorporating synthetic reactions developed across academic laboratories in Canada. The current release of the PCCL is contributed by seven Canadian academic groups. Using broadly available commercial building blocks, the resulting reaction space spans on the order of 1017 theoretically reachable drug-like compounds. Moreover, using cheap building blocks from ChemSpace (≤$100/100mg), an explicitly enumerated and experimentally actionable sub-library of approximately 77M compounds suitable for highthroughput virtual screening was generated. Comparison with the Enamine REAL library reveals that PCCL occupies a largely orthogonal chemical space, with fewer than 0.1 % Bemis–Murcko scaffolds shared between the two libraries. Rather than explicitly enumerating the full 1017 compound space, we introduce a PostgreSQL/RDKit-backed hit-expansion framework that enables targeted enumeration and analog retrieval directly within the reaction space. The expanded PCCL demonstrates how a community-sourced initiative can provide a scalable mechanism to access novel chemical space and support early-stage drug discovery against challenging and underexplored biological targets.</jats:p>