In silico screen identifies Pranidipine as a potential inhibitor of the PD-1/PD-L1 immune checkpoint.

Immune checkpoint blockade targeting the PD-1/PD-L1 axis using monoclonal antibodies has revolutionized cancer therapy by inducing durable antitumor responses across multiple cancer types. However, antibody-based therapeutics suffer from several limitations, including poor tissue permeability, immune-related adverse effects, complex manufacturing processes, and high production costs. These challenges underscore the need for small-molecule inhibitors (SMIs) as alternative therapeutic agents; nevertheless, to date, no FDA-approved small molecule has demonstrated proven in vivo efficacy against the PD-1/PD-L1 axis. Given the prolonged timelines and substantial costs associated with de novo drug discovery, drug repurposing represents an efficient and cost-effective strategy. In this study, we employed an integrated computational approach to identify potential SMIs capable of disrupting the PD-1/PD-L1 interaction. Structure-based virtual screening of 20 dihydropyridine (DHP) calcium channel blockers (CCBs) was performed using AutoDock Vina, along with CA-170 as a reference inhibitor. Several lead compounds were identified and evaluated based on binding affinity, bonding pose, and interaction patterns. Among the screened compounds, Pranidipine, Isradipine, and Efonidipine exhibited the most favorable binding profiles toward PD-1/PD-L1 complex inhibition. Furthermore, molecular dynamics (MD) simulations confirmed the stability of the interactions between these lead compounds and PD-L1, especially Pranidipine, over time. Collectively, our in silico findings suggest that selected DHP-CCBs may represent promising repurposing candidates for targeting the PD-1/PD-L1 immune checkpoint. However, further in vitro studies are required to validate their potential biological activity.