In silico discovery of novel small-molecule PD-L1 inhibitors through a multi-stage computational workflow integrating machine learning and molecular dynamics

Clinical Snapshot

Key Findings

• P Value: Not applicable for computational study

• Effect Size: D1 binding affinity: -86.21 kcal/mol vs reference: -73.65 kcal/mol

• Primary Outcome: Discovery of optimized PD-L1 inhibitor derivative D1 with superior binding properties

• Nnt Or Sensitivity: ML model: R2_train = 0.925, R2_test = 0.743

• Confidence Interval: Not reported for computational predictions

Clinical Application

Requires extensive experimental validation, toxicity testing, and clinical trials before implementation Would require TGA approval pathway for novel therapeutics; potential PBS listing considerations for cancer immunotherapy if proven effective Cancer patients requiring PD-L1 checkpoint inhibition, particularly those unsuitable for monoclonal antibody therapy

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.

References

1. 1.Garmabdari, A., Ayyoubzadeh, S. M., Ashkezari, F. D., Shahhosseini, S., Tabatabai, S. A., & Rezaee, E. (2024). In silico discovery of novel small-molecule PD-L1 inhibitors through a multi-stage computational workflow integrating machine learning and molecular dynamics. Journal of Computer-Aided Molecular Design. https://doi.org/10.1016/j.rechem.2024.101791