Design, synthesis, evaluation and molecular modeling of quinazoline derivatives bearing amino acids as small-molecule PD-L1 inhibitors.

Herein, we reported a series of quinazoline derivatives bearing amino acids by introducing a rigid pyrimidine structure between the 2 and 3-positions of the biphenyl and establishing an ionic interaction with Lys124 of PD-L1. Evaluation of the PD-1/PD-L1 inhibitory activity identified compound 7, which exhibited the most potent inhibitory activity with an IC value of 7.21 nM. Molecular docking was performed to demonstrate that the carboxyl group of amino acid in the tail established an ionic interaction with the ε-NH of Lys124, enhancing the binding. Importantly, molecular dynamics study revealed that the nitrogen atom in the nicotinonitrile formed water-mediated interactions with Asn63 of PD-L1, that stabilized the binding of the compound to PD-L1, providing an important and reasonable explanation for the introduction of nicotinonitrile to enhance inhibitory activity. Our study provides valuable guidance for further design of potent quinazoline-based small-molecule PD-L1 inhibitors, and identifies the compound 7 that is a promising lead compound and deserves further investigation.