小分子
化学
二聚体
合理设计
单体
分子
蛋白质-蛋白质相互作用
机制(生物学)
立体化学
血浆蛋白结合
分子动力学
结合位点
配体(生物化学)
生物物理学
组合化学
计算生物学
生物化学
受体
计算化学
纳米技术
生物
聚合物
材料科学
有机化学
哲学
认识论
作者
Xiaole Xu,Song Luo,Xiaoyu Zhao,Bolin Tang,Enhao Zhang,Jinxin Liu,Lili Duan
标识
DOI:10.1016/j.ijbiomac.2024.130921
摘要
The design of small molecule inhibitors that target the programmed death ligand-1 (PD-L1) is a forefront issue in immune checkpoint blocking therapy. Small-molecule inhibitors have been shown to exert therapeutic effects by inducing dimerization of the PD-L1 protein, however, the specific mechanisms underlying this dimerization process remain largely unexplored. Furthermore, there is a notable lack of comparative studies examining the binding modes of structurally diverse inhibitors. In view of the research gaps, this work employed molecular dynamics simulations to meticulously examine the interactions between two distinct types of inhibitors and PD-L1 in both monomeric and dimeric forms, and predicted the dimerization mechanism. The results revealed that inhibitors initially bind to a PD-L1 monomer, subsequently attracting another monomer to form a dimer. Notably, symmetric inhibitors observed superior binding efficiency compared to other inhibitors. Key residues, including Ile54, Tyr56, Met115 and Tyr123 played a leading role in binding. Structurally, symmetric inhibitors were capable of thoroughly engaging the binding pocket, promoting a more symmetrical formation of PD-L1 dimers. Furthermore, symmetric inhibitors formed more extensive hydrophobic interactions with protein residues. The insights garnered from this research are expected to significantly contribute to the rational design and optimization of small molecule inhibitors targeting PD-L1.
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