Delta Machine Learning to Improve Scoring-Ranking-Screening Performances of Protein–Ligand Scoring Functions

Protein–ligand scoring functions are widely used in structure-based drug design for fast evaluation of protein–ligand interactions, and it is of strong interest to develop scoring functions with machine-learning approaches. In this work, by expanding the training set, developing physically meaningful features, employing our recently developed linear empirical scoring function Lin_F9 (Yang, C. J. Chem. Inf. Model. 2021, 61, 4630−4644) as the baseline, and applying extreme gradient boosting (XGBoost) with Δ-machine learning, we have further improved the robustness and applicability of machine-learning scoring functions. Besides the top performances for scoring-ranking-screening power tests of the CASF-2016 benchmark, the new scoring function ΔLin_F9XGB also achieves superior scoring and ranking performances in different structure types that mimic real docking applications. The scoring powers of ΔLin_F9XGB for locally optimized poses, flexible redocked poses, and ensemble docked poses of the CASF-2016 core set achieve Pearson's correlation coefficient (R) values of 0.853, 0.839, and 0.813, respectively. In addition, the large-scale docking-based virtual screening test on the LIT-PCBA data set demonstrates the reliability and robustness of ΔLin_F9XGB in virtual screening application. The ΔLin_F9XGB scoring function and its code are freely available on the web at (https://yzhang.hpc.nyu.edu/Delta_LinF9_XGB).