Computational study on the binding mechanism of allosteric drug TNO155 inhibiting SHP2.

E76A mutations of SHP2 have been reported to associate with genetic developmental diseases and cancers, and TNO155 is one of the effective inhibitors targeted to the allosteric site 1, which has already entered the clinical stage. However, the detailed binding mechanism between them still needs further clarification at micro-atomic level. In this study, the binding mechanism of TNO155 inhibiting SHP2 and the superiorities of TNO155 at binding affinity and dynamic interactive behavior with SHP2 were probed utilizing a series of computational drug design technologies. The results show that SHP2 forms tighter interaction with TNO155 compared to SHP099. SHP2-TNO155 exhibits the largest electrostatic interaction among all complex systems, which can be manifested by the strong hydrogen bond interactions formed by two electrically charged residues, Arg111 and Glu250. Notably, in SHP2-TNO155 system, Asp489 makes an additional substantial beneficial contribution. The E76A mutation brings stronger residue positive correlation and a larger conformation fluctuation between N-CH2 and PTP domains, resulting in tighter binding between TNO155 and SHP2. This study offers valuable insights for the further design and development of novel SHP2 allosteric inhibitors.