Reframing Structure-Based Drug Design Model Evaluation via Metrics Correlated to Practical Needs
Bowen Gao Haichuan Tan Yanwen Huang Minsi Ren Xiao Huang Wei-Ying Ma Ya-Qin Zhang Yanyan Lan
Recent advances in structure-based drug design (SBDD) have produced surprising results, with models often generating molecules that achieve better Vina docking scores than actual ligands. However, these results are frequently overly optimistic due to the limitations of docking score accuracy and the challenges of wet-lab validation. While generated molecules may demonstrate high QED (drug-likeness) and SA (synthetic accessibility) scores, they often lack true drug-like properties or synthesizability. To address these limitations, we propose a model-level evaluation framework that emphasizes practical metrics aligned with real-world applications. Inspired by recent findings on the utility of generated molecules in ligand-based virtual screening, our framework evaluates SBDD models by their ability to produce molecules that effectively retrieve active compounds from chemical libraries via similarity-based searches. This approach provides a direct indication of therapeutic potential, bridging the gap between theoretical performance and real-world utility. Our experiments reveal that while SBDD models may excel in theoretical metrics like Vina scores, they often fall short in these practical metrics. By introducing this new evaluation strategy, we aim to enhance the relevance and impact of SBDD models for pharmaceutical research and development.
Stucture-Based Drug Design, Model Evaluation, Benchmark