Integrating Molecular Dynamics, Molecular Docking, and Machine Learning for Predicting SARS-CoV-2 Papain-like Protease Binders

Coronavirus disease 2019 (COVID-19) produced devastating health and economic impacts worldwide. While progress has been made in vaccine development, effective antiviral treatments remain limited, particularly those targeting the papain-like protease (PLpro) of SARS-CoV-2. PLpro plays a key role in viral replication and immune evasion, making it an attractive yet underexplored target for drug repurposing. In this study, we combined machine learning, molecular dynamics, and molecular docking to identify potential PLpro inhibitors in existing drugs. We performed long-timescale molecular dynamics simulations on PLpro-ligand complexes at two known binding sites, followed by structural clustering to capture representative structures. These were used for molecular docking, including a training set of 127 compounds and a library of 1107 FDA-approved drugs. A random forest model, trained on the docking scores of the representative conformations, yielded 76.4% accuracy via leave-one-out cross-validation. Applying the model to the drug library and filtering results based on prediction confidence and the applicability domain, we identified five drugs as promising candidates for repurposing for COVID-19 treatment. Our findings demonstrate the power of integrating computational modeling with machine learning to accelerate drug repurposing against emerging viral targets.