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The growing size of make-on-demand chemical libraries is posing new challenges to cheminformatics. These ultra-large chemical libraries became too large for exhaustive enumeration. Using a combinatorial approach instead, the resource requirement scales approximately with the number of synthons instead of the number of molecules. This gives access to billions or trillions of compounds as so-called chemical spaces with moderate hardware and in a reasonable time frame. While extremely performant ligand-based 2D methods exist in this context, 3D methods still largely rely on exhaustive enumeration and therefore fail to apply. Here, we present SpaceGrow: a novel shape-based 3D approach for ligand-based virtual screening of billions of compounds within hours on a single CPU. Compared to a conventional superposition tool, SpaceGrow shows comparable pose reproduction capacity based on RMSD and superior ranking performance while being orders of magnitude faster. Result assessment of two differently sized subsets of the eXplore space reveals a higher probability of finding superior results in larger spaces highlighting the potential of searching in ultra-large spaces. Furthermore, the application of SpaceGrow in a drug discovery workflow was investigated in four examples involving G protein-coupled receptors (GPCRs) with the aim to identify compounds with similar binding capabilities and molecular novelty., (© 2024. The Author(s).)

Molecular docking is a standard technique in structure-based drug design (SBDD). It aims to predict the 3D structure of a small molecule in the binding site of a receptor (often a protein). Despite being a common technique, it often necessitates multiple tools and involves manual steps. Here, we present the JAMDA preprocessing and docking workflow that is easy to use and allows fully automated docking. We evaluate the JAMDA docking workflow on binding sites extracted from the complete PDB and derive key factors determining JAMDA's docking performance. With that, we try to remove most of the bias due to manual intervention and provide a realistic estimate of the redocking performance of our JAMDA preprocessing and docking workflow for any PDB structure. On this large PDBScan22 data set, our JAMDA workflow finds a pose with an RMSD of at most 2 Å to the crystal ligand on the top rank for 30.1% of the structures. When applying objective structure quality filters to the PDBScan22 data set, the success rate increases to 61.8%. Given the prepared structures from the JAMDA preprocessing pipeline, both JAMDA and the widely used AutoDock Vina perform comparably on this filtered data set (the PDBScan22-HQ data set).