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

Abstract

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 IC₅₀ 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-NH₃⁺ 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.