Liu Han, Chen Roufen, Yuan Dandan, Xing Yidan, Ding Xueyan, Wu Xingye, Gao Yali, Ma Junjie
School of Medicine, Huaqiao University, Quanzhou, 362000, China.
College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
J Comput Aided Mol Des. 2025 Jul 18;39(1):55. doi: 10.1007/s10822-025-00635-y.
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.
在此，我们报道了一系列通过在联苯的2位和3位之间引入刚性嘧啶结构并与PD-L1的Lys124建立离子相互作用而带有氨基酸的喹唑啉衍生物。对PD-1/PD-L1抑制活性的评估确定了化合物7，其表现出最有效的抑制活性，IC值为7.21 nM。进行分子对接以证明尾部氨基酸的羧基与Lys124的ε-NH建立了离子相互作用，增强了结合。重要的是，分子动力学研究表明烟腈中的氮原子与PD-L1的Asn63形成了水介导的相互作用，这稳定了化合物与PD-L1的结合，为引入烟腈以增强抑制活性提供了重要且合理的解释。我们的研究为进一步设计有效的基于喹唑啉的小分子PD-L1抑制剂提供了有价值的指导，并确定了化合物7是一种有前途的先导化合物，值得进一步研究。
