Exploring the mechanism of the potent allosteric inhibitor compound2 on SHP2 and SHP2 by molecular dynamics study.

Abnormal activation of Ras/MAPK signaling pathway could trigger excessive cell division. Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2) could promote Ras/MAPK activation by integrating growth factor signals. Thus, SHP2 inhibitors had become a hot topic in the treatment of cancer. SHP2, mutation in SHP2, was detected in leukemia variants. The compound 2 (3-benzyl-8-chloro-2-hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one) had been reported that it was a potent allosteric inhibitor of both SHP2 wild type (SHP2) and the F285S mutant (SHP2). However, the mechanism of inhibition remained to be further discovered. Herein, molecular docking and molecular dynamic (MD) simulation were performed to explain the inhibition mechanism of compound 2 on SHP2 and SHP2. Overall, the molecular docking analysis revealed that compound 2 maintained the "close" structure of SHP2 protein probably by locking the C-SH2 and PTP domain. Next, post-analysis demonstrated that compound 2 might make TYR66-GLU76 of D'E-loop in N-SH2 and GLU258-LYS266 of B'C-loop, HIS458-ARG465 of P-loop, VAL497-THR507 of Q-loop in PTP domain regions tightly connect and much easier maintain "self-inhibited" conformation of SHP2 than that of SHP2. Importantly, GLU76 of D'E-loop could play a vital role in inhibition of SHP2 and SHP2. This work provided a reliable clue to develop novel inhibitors for leukemia related to SHP2.