The programmed cell death protein 1 (PD-1) and its ligand, PD-L1, constitute an important co-inhibitory immune checkpoint leading to downregulation of immune system. Tumor cells developed a strategy to trigger PD-1/PD-L1 pathway reducing the T cell anticancer activity. Anti-PD-L1 small drugs, generally with improved pharmacokinetic and technological profiles than monoclonal antibodies, became an attractive research topic. Nevertheless, still few works have been published on the chemical features of possible binding sites. In this work, we applied a novel computational protocol based on the combination of the ab initio Fragment Molecular Orbital (FMO) method and a newly developed GRID-DRY approach in order to characterize the PD-L1 binding sites, starting from PD-1/PD-L1 and PD-L1/BMS-ligands (Bristol–Mayers Squibb ligands) complexes. The FMO method allows the calculation of the pair-residues as well as the ligand–residues interactions with ab initio accuracy, whereas the GRID-DRY approach is an effective tool to investigate hydrophobic interactions, not easily detectable by ab initio methods. The present GRID-DRY protocol is able to determine the energy contributions of each ligand atoms to each hydrophobic interaction, both qualitatively and quantitatively. We were also able to identify the three specific hot regions involved in PD-1/PD-L1 protein–protein interaction and in PD-L1/BMS-ligand interactions, in agreement with preceding theoretical/experimental results, and to suggest a specific pharmacophore for PD-L1 inhibitors.

程序性细胞死亡蛋白 1 (PD-1) 及其配体 PD-L1 构成了重要的共抑制免疫检查点，导致免疫系统下调。肿瘤细胞开发了一种策略来触发 PD-1/PD-L1 通路，从而降低 T 细胞的抗癌活性。抗 PD-L1 小药通常具有比单克隆抗体更好的药代动力学和技术特征，成为一个有吸引力的研究课题。尽管如此，关于可能结合位点的化学特征的研究仍然很少。在这项工作中，我们应用了一种基于从头算片段分子轨道 (FMO) 方法和新开发的 GRID-DRY 方法相结合的新计算协议，以表征 PD-L1 结合位点，从 PD-1/ PD-L1 和 PD-L1/BMS-配体（Bristol-Mayers Squibb 配体）复合物。FMO 方法允许以 ab initio 精度计算配对残基以及配体-残基相互作用，而 GRID-DRY 方法是研究疏水相互作用的有效工具，不容易通过 ab initio 方法检测到。目前的 GRID-DRY 协议能够定性和定量地确定每个配体原子对每个疏水相互作用的能量贡献。我们还能够确定参与 PD-1/PD-L1 蛋白-蛋白相互作用和 PD-L1/BMS-配体相互作用的三个特定热点区域，与之前的理论/实验结果一致，并提出了特定的药效团对于 PD-L1 抑制剂。而 GRID-DRY 方法是研究疏水相互作用的有效工具，不容易通过 ab initio 方法检测到。目前的 GRID-DRY 协议能够定性和定量地确定每个配体原子对每个疏水相互作用的能量贡献。我们还能够确定参与 PD-1/PD-L1 蛋白-蛋白相互作用和 PD-L1/BMS-配体相互作用的三个特定热点区域，与之前的理论/实验结果一致，并提出了特定的药效团对于 PD-L1 抑制剂。而 GRID-DRY 方法是研究疏水相互作用的有效工具，不容易通过 ab initio 方法检测到。目前的 GRID-DRY 协议能够定性和定量地确定每个配体原子对每个疏水相互作用的能量贡献。我们还能够确定参与 PD-1/PD-L1 蛋白-蛋白相互作用和 PD-L1/BMS-配体相互作用的三个特定热点区域，与之前的理论/实验结果一致，并提出了特定的药效团对于 PD-L1 抑制剂。