Cited by 22Protein Tyrosine PhosphatasesComputational Drug Discovery MethodsProtein Kinase Regulation and GTPase Signaling

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

Wang, Rui-Rui, Liu, Wen-Shan, Zhou, Liang, Ma, Ying, Wang, Run-Ling·2020·Journal of Biomolecular Structure and Dynamics

Abstract

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

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Crossref · 10.1080/07391102.2019.1613266

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Authors
Wang, R.-R., Liu, W.-S., Zhou, L., Ma, Y., & Wang, R.-L.
Affiliations
  • Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China
  • Tianjin Medical University (CN)
Corresponding author
  • Ma, Ying
  • Wang, Run-Ling
Venue
Journal of Biomolecular Structure and Dynamics
Published
2019-05-13
Volume
38
Issue
5
Pages
1525-1538
ISSN
  • 0739-1102 (ISSN-L)
  • 1538-0254
OpenAlex
W2942505575
Cited by
21
References
55
Citations by year
2025: 2 · 2023: 5 · 2022: 2 · 2021: 4 · 2020: 7 · 2019: 1
FWCI
1.16
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Biomolecular Structure and Dynamics (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China
  • Natural Science Foundation of Tianjin City ())
  • Natural Science Foundation of Tianjin (0, 0))
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
SHP2 inhibitors, SHP099, RAS/MAPK pathway, protein-ligand binding mode, protein conformational stability, cancer drug targets, binding affinity
MeSH terms
Protein Conformation, Signal Transduction, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Molecular Dynamics Simulation, Molecular Docking Simulation

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