Zhou, Liang
(Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University)
,
Feng, Yong
(Department of Otorhinolaryngology Head and Neck, The 4th Central Hospital of Tianjin)
,
Ma, Yang-Chun
(Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University)
,
Zhang, Zhao
(Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University)
,
Wu, Jing-Wei
(Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University)
,
Du, Shan
(Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School)
,
Li, Wei-Ya
,
Lu, Xin-Hua
,
Ma, Ying
,
Wang, Run-Ling
Abstract 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 tr...
Abstract 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. SHP2F285S, 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 (SHP2WT) and the F285S mutant (SHP2F285S). 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 SHP2WT and SHP2F285S. 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 SHP2F285S−compound2 than that of SHP2WT-compound2. Importantly, GLU76 of D’E-loop could play a vital role in inhibition of SHP2WT-compound2 and SHP2F285S−compound2. This work provided a reliable clue to develop novel inhibitors for leukemia related to SHP2F285S. Highlights Compound 2 had stronger affinity with SHP2F285S than with SHP2WT. Compound 2 could stabilize the internal movement of SHP2 wild-type and mutant proteins. GLU76 of DE-loop could play a crucial role in maintaining the internal stability of the protein-ligand complex. Graphical abstract Complete workflow of the study for exploring the mechanism of the potent allosteric inhibitor compound 2 on SHP2 WT and SHP2F285S by molecular dynamics study. Clarify the better binding posture between compound 2 and proteins through molecular docking and binding energy modules. Following, dynamic simulation and post-analysis were performed to explore the internal movement changes before and after the compound binds to the protein. It was found that GLU76 of DE-loop played a key role in the compound 2’s inhibition of proteins activity. [DISPLAY OMISSION]
Abstract 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. SHP2F285S, 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 (SHP2WT) and the F285S mutant (SHP2F285S). 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 SHP2WT and SHP2F285S. 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 SHP2F285S−compound2 than that of SHP2WT-compound2. Importantly, GLU76 of D’E-loop could play a vital role in inhibition of SHP2WT-compound2 and SHP2F285S−compound2. This work provided a reliable clue to develop novel inhibitors for leukemia related to SHP2F285S. Highlights Compound 2 had stronger affinity with SHP2F285S than with SHP2WT. Compound 2 could stabilize the internal movement of SHP2 wild-type and mutant proteins. GLU76 of DE-loop could play a crucial role in maintaining the internal stability of the protein-ligand complex. Graphical abstract Complete workflow of the study for exploring the mechanism of the potent allosteric inhibitor compound 2 on SHP2 WT and SHP2F285S by molecular dynamics study. Clarify the better binding posture between compound 2 and proteins through molecular docking and binding energy modules. Following, dynamic simulation and post-analysis were performed to explore the internal movement changes before and after the compound binds to the protein. It was found that GLU76 of DE-loop played a key role in the compound 2’s inhibition of proteins activity. [DISPLAY OMISSION]
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