Blockade of the checkpoint PD-1 by its ligand PD-L1 and the immuno-oncological drugs pembrolizumab and nivolumab,Physical Chemistry Chemical Physics

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Blockade of the checkpoint PD-1 by its ligand PD-L1 and the immuno-oncological drugs pembrolizumab and nivolumab
Physical Chemistry Chemical Physics ( IF 2.9 ) Pub Date : 2021-09-13 , DOI: 10.1039/d1cp03064g
Ana Beatriz M L A Tavares _{1,

2} , J X Lima Neto ₁ , U L Fulco ₁ , E L Albuquerque ₁

Affiliation

We investigate the interaction between the programmed cell death protein 1 (PD-1) and the programmed cell death ligand 1 (PD-L1), as well as the immuno-oncological drugs pembrolizumab (PEM), and nivolumab (NIV), through quantum chemistry methods based on the Density Functional Theory (DFT) and the molecular fractionation with conjugate caps (MFCC) scheme, in order to map their hot-spot regions. Our results showed that the total interaction energy order of the three complexes is in good agreement with the experimental binding affinity order: PD-1/PEM > PD-1/NIV > PD-1/PD-L1. Besides, a detailed investigation revealed the energetically most relevant residue–residue pairs-interaction for each complex. Our computational results give a better understanding of the interaction mechanism between the protein PD-1 and its ligands (natural and inhibitors), unleashing the immune surveillance to destroy the cancer cells by decreasing their immune evasion. They are also an efficient alternative towards the development of new small-molecules and antibody-based drugs, pointing out to new treatments for cancer therapy.

中文翻译：

通过其配体 PD-L1 和免疫肿瘤药物 pembrolizumab 和 nivolumab 阻断检查点 PD-1

我们研究了程序性细胞死亡蛋白 1 (PD-1) 和程序性细胞死亡配体 1 (PD-L1) 以及免疫肿瘤药物派姆单抗 (PEM) 和纳武单抗 (NIV) 之间的相互作用，通过量子基于密度泛函理论 (DFT) 和共轭帽分子分级 (MFCC) 方案的化学方法，以绘制它们的热点区域。我们的结果表明，三种复合物的总相互作用能顺序与实验结合亲和力顺序非常一致：PD-1/PEM > PD-1/NIV > PD-1/PD-L1。此外，详细的调查揭示了每个复合物在能量上最相关的残基-残基对相互作用。我们的计算结果可以更好地理解蛋白质 PD-1 与其配体（天然和抑制剂）之间的相互作用机制，通过减少免疫逃避来释放免疫监视以摧毁癌细胞。它们也是开发新的小分子和基于抗体的药物的有效替代品，指出了癌症治疗的新疗法。

更新日期：2021-09-17

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