In Silico Discovery of Novel Small-Molecule Pd-L1 Inhibitors Through a Multi-Stage Computational Workflow Integrating Machine Learning and Molecular Dynamics Publisher Pubmed



Garmabdari A ; Ayyoubzadeh SM ; Ashkezari FD ; Shahhosseini S ; Tabatabai SA ; Rezaee E
Source: Journal of Computer-Aided Molecular Design Published:2026

Abstract

Cancer immunotherapy targeting the PD-1/PD-L1 pathway has transformed modern oncology; however, developing small-molecule inhibitors as viable alternatives to monoclonal antibodies remains a major challenge. In this study, an integrated computational framework is established in which machine learning, molecular docking, molecular dynamics simulations, and binding free-energy calculations are combined to enable the discovery and optimization of novel PD-L1 inhibitors. A validated ML-QSAR model was constructed using the XGBoost algorithm (R2_train = 0.925, R2_test = 0.743) on a dataset of 74 known inhibitors with consistent assay conditions. Through virtual screening of FDA-approved drugs, Pralatrexate was subsequently identified as a promising repurposing candidate, demonstrating a higher predicted binding affinity than the reference inhibitors. Structure-based modification of Pralatrexate yielded the derivative D1, which exhibited improved computational binding properties across all evaluation methods. Molecular dynamics simulations indicated that the D1–PD-L1 complex achieved greater stability than both the free protein and the reference complex, with reduced RMSD fluctuations and preserved key interactions with tyrosine residues Tyr56(A/B). MM-GBSA calculations further confirmed D1’s superior binding affinity (–86.21 kcal/mol vs. − 73.65 kcal/mol for the reference), and predicted IC50 values suggested enhanced inhibitory potential. This multi-stage computational workflow effectively integrates machine learning predictions with atomic-level binding analyses, providing a robust platform for accelerated drug discovery. The optimized derivative D1 thus represents a promising candidate for experimental validation and further development as a potential cancer immunotherapeutic agent. © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2026.