Abstract
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.