Probing the acting mode and advantages of RMC-4550 as an Src-homology 2 domain-containing protein tyrosine phosphatase (SHP2) inhibitor at molecular level through molecular docking and molecular dynamics.

The over-activation of Ras/mitogen-activated protein kinase (MAPK) signaling pathway associated with a variety of cancers is usually related with abnormal activation of Src-homology 2 domain-containing protein tyrosine phosphatase (SHP2). For this purpose, SHP2 has attracted extensive interest as a potential target for cancer treatment. RMC-4550, as a newly developed selective inhibitor of SHP2, possesses an overwhelming advantage over the previous generation inhibitor SHP099 in terms of in vitro activity. However, the binding mode of SHP2 with RMC-4550 and the reason for the high efficiency of RMC-4550 as SHP2 inhibitor at molecular level are still unclear. Therefore, in this study, the binding mode of RMC-4550 with SHP2 and the superiorities of RMC-4550 as inhibitor at binding affinity and dynamic interactive behavior with SHP2 were probed by molecular docking and molecular dynamics (MD) simulations. By comparing the results of molecular docking, it was found that SHP2 formed more tight interaction with RMC-4550 than that with SHP099. Subsequently, a series of post-dynamic analyses on three simulation trajectories (SHP2WT, SHP2SHP099 and SHP2RMC-4550) were performed and found that the SHP2 protein bound with RMC-4550 maintained a firmer interaction between N-Src-homology 2 (N-SH2) and PTP domain throughout the MD simulation, leading to a more stable protein conformation. The finding here provides new clues for the design of SHP2 inhibitor against the over-activation of Ras/MAPK pathway.Communicated by Ramaswamy H. Sarma.