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Prediction of SHP2-E76K binding sites based on molecular dynamics simulation and Markov algorithm
Si-Pei Zhang1, Li-Juan Chen1, Zhen-Liang Shi2
1Department of Pharmacy, Tianjin Chest Hospital, Tianjin, China.
Abstract:
SHP2-E76K, a mutant encoded by the PTPN11 gene, was associated with various solid tumors, such as lung cancer, glioblastoma, and intellectual disability. SHP2-E76K has become potential drug targets, while there was no effective inhibitor against the mutant currently. At present, the crystal complex structure of SHP099 with SHP2-E76K has been reported in the RCSB PDB protein data bank, however, the dynamic structure of SHP099 binding to the active center of SHP2-E76K protein was still lacking. Therefore, this study used molecular dynamics simulation and Markov model to characterize the kinetics of the inhibitor SHP099 with SHP2-E76K enzyme and to determine the active binding site, which would give a hint of a vital enzyme-substrate interaction in atomistic detail that proposed the potential to be applied for the discovery of more effective SHP2-E76K inhibitors and, in broader terms, dynamic protein-drug interactions.
Insights
This study reveals the dynamic binding of SHP099 to the SHP2-E76K mutant, crucial for targeting solid tumors. Understanding this interaction aids in developing more effective SHP2-E76K inhibitors.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- The PTPN11 gene encodes SHP2, a protein phosphatase implicated in various solid tumors when mutated to SHP2-E76K.
- SHP2-E76K is a promising drug target, yet effective inhibitors are currently unavailable.
- While the static crystal structure of SHP099 with SHP2-E76K exists, its dynamic binding behavior remains uncharacterized.
Purpose of the Study:
- To elucidate the dynamic interactions between the inhibitor SHP099 and the SHP2-E76K enzyme.
- To identify the precise active binding site of SHP099 within SHP2-E76K at an atomistic level.
- To provide insights for designing more potent SHP2-E76K inhibitors.
Main Methods:
- Molecular dynamics (MD) simulations were employed to capture the dynamic behavior of the SHP099-SHP2-E76K complex.
- Markov state modeling (MSM) was utilized to analyze the kinetic pathways of the inhibitor binding.
- Atomistic details of the enzyme-inhibitor interaction were characterized.
Main Results:
- The study characterized the kinetics of SHP099 binding to the SHP2-E76K active site.
- Key atomistic interactions governing the enzyme-inhibitor complex were identified.
- The dynamic binding process and active site interactions were revealed.
Conclusions:
- This research provides a detailed dynamic understanding of SHP099 binding to SHP2-E76K.
- The findings offer critical insights into enzyme-substrate interactions for SHP2-E76K.
- The study lays the groundwork for the rational design of novel and more effective SHP2-E76K inhibitors.
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