Molecular insight into binding affinities and blockade effects of selected flavonoid compounds on the PD-1/PD-L1...

This study investigated the binding mechanisms of the flavonoids apigenin (Api), kaempferol (Kmp), and quercetin (Que) to the PD-L1 dimer using a combination of molecular modeling and experimental techniques. The binding free energy results demonstrated that the flavonoids could tightly bind to the PD-L1 dimer, with the binding abilities following the trend Que > Kmp > Api. Key residues Ile54, Tyr56, Met115, Ala121, and Tyr123 were identified as important for binding. The flavonoids primarily bind to the C-, F-, and G-sheet domains. The spontaneous formation of the complex systems was mainly driven by hydrophobic forces. Dynamic cross-correlation matrix and secondary structure analyses further indicated that the studied flavonoids could stably interact with the binding sites. ELISA results showed that the flavonoids could effectively block PD-1/PD-L1 interactions, although the inhibitory activity of Api was weaker. Therefore, flavonols might be more effective inhibitors compared to flavones. The findings of this study are expected to contribute to the development of novel flavonoids targeting the PD-1/PD-L1 pathway.