Human purine nucleoside phosphorylase (hPNP) plays a significant role in the catabolism of deoxyguanosine. The trimeric protein is an important target in the treatment of T-cell cancers and autoimmune disorders. Experimental studies on the inhibition of the hPNP observe that the first ligand bound to one of three subunits effectively inhibits the protein, while the binding of more ligands to the subsequent sites shows negative cooperativities. In this work, we performed extensive end-point and alchemical free energy calculations to determine the binding thermodynamics of the trimeric protein–ligand system. 13 Immucillin inhibitors with experimental results are under calculation. Two widely accepted charge schemes for small molecules including AM1-BCC and RESP are adopted for ligands. The results of RESP are in better agreement with the experimental reference. Further investigations of the interaction networks in the protein–ligand complexes reveal that several residues play significant roles in stabilizing the complex structure. The most commonly observed ones include PHE200, GLU201, MET219, and ASN243. The conformations of the protein in different protein–ligand complexes are observed to be similar. We expect these insights to aid the development of potent drugs targeting hPNP.

人嘌呤核苷磷酸化酶 (hPNP) 在脱氧鸟苷的分解代谢中起重要作用。三聚体蛋白是治疗 T 细胞癌和自身免疫性疾病的重要靶点。对 hPNP 抑制的实验研究观察到，与三个亚基之一结合的第一个配体有效地抑制了蛋白质，而更多配体与后续位点的结合显示出负协同作用。在这项工作中，我们进行了广泛的终点和炼金术自由能计算，以确定三聚体蛋白质-配体系统的结合热力学。13种免疫球蛋白抑制剂的实验结果正在计算中。配体采用两种广泛接受的小分子电荷方案，包括 AM1-BCC 和 RESP。RESP 的结果与实验参考比较吻合。对蛋白质-配体复合物中相互作用网络的进一步研究表明，几个残基在稳定复合物结构方面起着重要作用。最常观察到的包括 PHE200、GLU201、MET219 和 ASN243。观察到不同蛋白质-配体复合物中的蛋白质构象是相似的。我们希望这些见解有助于开发针对 hPNP 的有效药物。观察到不同蛋白质-配体复合物中的蛋白质构象是相似的。我们希望这些见解有助于开发针对 hPNP 的有效药物。观察到不同蛋白质-配体复合物中的蛋白质构象是相似的。我们希望这些见解有助于开发针对 hPNP 的有效药物。