iScore: A ML-BasedScoring Function for De Novo DrugDiscovery

In the quest for accelerating de novo drug discovery, the development of efficient and accurate scoring functions represents a fundamental challenge. This study introduces iScore, a novel machine learning (ML)-based scoring function designed to predict the binding affinity of protein–ligand complexes with remarkable speed and precision. Uniquely, iScore circumvents the conventional reliance on explicit knowledge of protein–ligand interactions and a full picture of atomic contacts, instead leveraging a set of ligand and binding pocket descriptors to directly evaluate binding affinity. This approach enables skipping the inefficient and slow conformational sampling stage, thereby enabling the rapid screening of ultrahuge molecular libraries, a crucial advancement given the practically infinite dimensions of chemical space. iScore was rigorously trained and validated using the PDBbind 2020 refined set, CASF 2016, CSAR NRC-HiQ Set1/2, DUD-E, and target fishing data sets, employing three distinct ML methodologies: Deep neural network (iScore-DNN), random forest (iScore-RF), and eXtreme gradient boosting (iScore-XGB). A hybrid model, iScore-Hybrid, was subsequently developed to incorporate the strengths of these individual base learners. The hybrid model demonstrated a Pearson correlation coefficient (<i>R</i>) of 0.78 and a root-mean-square error (RMSE) of 1.23 in cross-validation, outperforming the individual base learners and establishing new benchmarks for scoring power (<i>R</i> = 0.814, RMSE = 1.34), ranking power (ρ = 0.705), and screening power (success rate at top 10% = 73.7%). Moreover, iScore-Hybrid demonstrated great performance in the target fishing benchmarking study.