G-screen: Scalable Receptor-Aware Virtual Screening through Flexible Ligand Alignment

Virtual screening has long been a central computational tool for rational ligand discovery, enabling the systematic prioritization of candidate molecules from large chemical libraries. Although docking and related approaches that explicitly account for receptor-ligand interactions have been developed and refined over several decades, achieving both reliable receptor-aware interaction modeling and computational scalability remains an open challenge, particularly for ultra-large chemical spaces. Ligand-based methods are fast and robust but do not explicitly incorporate receptor structure, whereas docking-based approaches model receptor-ligand interactions more directly at substantially higher computational cost. Here, we present G-screen, a freely available and scalable receptor-aware virtual screening framework designed for cases in which a reference protein-ligand complex structure is available. Instead of performing full docking, G-screen rapidly aligns candidate ligands to the reference ligand using a flexible global alignment algorithm (G-align) and evaluates receptor-aware pharmacophore interactions derived from the reference complex, thereby combining the efficiency of ligand-based alignment with explicit atomic-level interaction analysis. Benchmarking on DUD-E, LIT-PCBA, and MUV datasets demonstrates that G-screen achieves competitive discrimination and early enrichment relative to representative ligand-based and docking-based methods, while maintaining millisecond-scale per-molecule runtimes under multi-threaded execution. These results position G-screen as a practical and scalable receptor-aware screening strategy for efficiently filtering large chemical libraries when a reference complex structure is available. Scientific ContributionWe have developed a scalable virtual screening framework for efficiently filtering ultra-large chemical libraries using a flexible global alignment algorithm combined with receptor-aware pharmacophore evaluations. Despite explicitly capturing atomic-level interactions, the screening process using this method is highly efficient, maintaining millisecond-scale per-molecule runtimes under parallel execution. It achieves competitive discrimination and early enrichment, successfully bridging the speed of ligand-based approaches with the structural context of traditional docking.