On the Difficulty to Rescore Hits from Ultralarge Docking Screens

binding assays, for binding affinity prediction using eight rescoring methods including simple empirical scoring functions, machine learning, molecular-mechanics and quantum-mechanics approaches. Although the best predictions usually rely on the most sophisticated methods, none of the tested rescoring methods could robustly distinguish known binders from inactive compounds, across all assays. Energy refinement of protein-ligand complexes, prior to rescoring, marginally helped molecular mechanics and quantum mechanics approaches but deteriorates predictions from empirical and machine learning scoring functions.