Machine Learning-Aided Small-Molecule Virtual Screening: Recent Advances and Future Perspectives

Virtual screening (VS) on small molecules aims to identify promising drug candidates against protein targets from expansive chemical libraries by balancing the core requirements of accurate scoring and efficient search against the inherent trade-off between accuracy and speed. This survey provides a comprehensive review of how Artificial Intelligence and Machine Learning (AI/ML) are redefining this landscape across three critical dimensions. First, we examine the evolution of AI-driven scoring functions, which utilize AI/ML models to capture complex structure-activity relationships from massive biochemical datasets, significantly enhancing structure- and ligand-based evaluations beyond traditional heuristics. Second, we summarize the emergence of efficient search algorithms that iteratively prioritize informative compounds to reduce search efforts by orders of magnitude. Third, we review the paradigm shift toward generative molecular design, making VS transition from screening fixed libraries to the de novo generation of molecules optimized for specific structural contexts and multi-objective properties. This review outlines the transition toward end-to-end, adaptive discovery systems that ensure computational hits are biologically potent, structurally optimized, and synthetically accessible.

WIREs Computational Molecular Science