Bajia Donald, Derwich Katarzyna
Department of Pediatric Oncology, Hematology and Transplantology, Poznan University of Medical Sciences, Ul. Fredry 10, 61701 Poznan, Poland.
Pharmaceuticals (Basel). 2023 Jun 26;16(7):926. doi: 10.3390/ph16070926.
The human PTPN11 gene encodes for the src tyrosine phosphatase protein (SHP2) is now gaining much attention in many disorders, particularly its oncogenic involvement in many types of cancer. Efforts in developing molecules targeting SHP2 with high efficacy are the future of drug discovery and chemotherapy. However, the interaction of a new camptothecin analog with the catalytic domain of SHP2 protein remains unknown. Therefore, this study aims to provide in silico rationale for the recognition and binding of FL118 and irinotecan with the catalytic domain of human protein tyrosine phosphatase-SHP2 (PTPc-SH2-SHP2, chain A). The docking interaction of the human SHP2 protein's catalytic domain as well as Y279C and R465G mutants with FL118 and irinotecan ligands were calculated and analyzed using the Autodock 4.2 programme, setting the docking grid to target the protein's active site. The camptothecin analog FL118 had the best lowest negative affinity energies with PTPc-SHP2 wildtype and SHP2-Y279C mutant model (-7.54 Kcal/mol and -6.94 Kcal/mol, respectively). Moreover, the protein-ligand complexes revealed several hydrogen bond interactions reflecting the degree of stability that each structure possesses, with the FL118-SHP2-wildtype forming the most stable complex among the structures. In addition, the FL118-SHP2 wildtype complex was validated for RMSD, RMSF, hydrogen bonds, and salt bridges. This revealed that the complex generated became stable over time. This in silico rationale identifies the novel FL118 camptothecin analog as a potent selective inhibitor of PTPc-SH2 domain of SHP2 protein, paving way for further in vitro investigations into the interactions and binding activity of analogs with SHP2 for potential therapeutic applications in PTPN11-associated disorders.
人类PTPN11基因编码的src酪氨酸磷酸酶蛋白（SHP2）目前在许多疾病中备受关注，尤其是其在多种癌症中的致癌作用。开发高效靶向SHP2的分子是药物发现和化疗的未来方向。然而，一种新型喜树碱类似物与SHP2蛋白催化结构域的相互作用仍不清楚。因此，本研究旨在为FL118和伊立替康与人类蛋白酪氨酸磷酸酶 - SHP2（PTPc - SH2 - SHP2，A链）的催化结构域的识别和结合提供计算机模拟依据。使用Autodock 4.2程序计算并分析了人类SHP2蛋白催化结构域以及Y279C和R465G突变体与FL118和伊立替康配体的对接相互作用，设置对接网格以靶向蛋白质的活性位点。喜树碱类似物FL118与PTPc - SHP2野生型和SHP2 - Y279C突变体模型具有最佳的最低负亲和能（分别为 - 7.54千卡/摩尔和 - 6.94千卡/摩尔）。此外，蛋白质 - 配体复合物揭示了几种氢键相互作用，反映了每个结构所具有的稳定性程度，其中FL118 - SHP2 - 野生型在这些结构中形成了最稳定的复合物。此外，对FL118 - SHP2野生型复合物进行了均方根偏差（RMSD）、均方根波动（RMSF）、氢键和盐桥的验证。结果表明，随着时间的推移，生成的复合物变得稳定。这种计算机模拟依据确定了新型FL118喜树碱类似物是SHP2蛋白PTPc - SH2结构域的有效选择性抑制剂，为进一步体外研究类似物与SHP2的相互作用和结合活性以用于PTPN11相关疾病的潜在治疗应用铺平了道路。
