Prediction of SHP2-E76K binding sites based on molecular dynamics simulation and Markov algorithm.

in Journal of biomolecular structure & dynamics by Si-Pei Zhang, Li-Juan Chen, Zhen-Liang Shi, Xin Li, Ying Ma

TLDR

  • SHP2-E76K is a mutant protein that is associated with various solid tumors. This study used computer simulations to understand how SHP099, a potential drug, interacts with SHP2-E76K. The study found that SHP099 effectively binds to SHP2-E76K and identified the part of the protein where the drug binds. This information could help researchers design better drugs to treat SHP2-E76K-associated tumors.

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.

Overview

  • The study focuses on the association of SHP2-E76K, a mutant encoded by the PTPN11 gene, with various solid tumors and its potential as a drug target. The methodology used includes molecular dynamics simulation and Markov model to characterize the kinetics of SHP099 with SHP2-E76K enzyme and determine the active binding site. The primary objective is to determine the dynamic protein-drug interactions in atomistic detail that could lead to the discovery of more effective SHP2-E76K inhibitors and broader protein-drug interactions.

Comparative Analysis & Findings

  • The study compares the outcomes observed under the inhibition of SHP099 with SHP2-E76K enzyme. The results show that SHP099 effectively inhibits SHP2-E76K enzyme, with a binding affinity of 1.5 nM. The study also identifies the active binding site of SHP099 with SHP2-E76K enzyme, which is located in the ATP-binding pocket. The key findings of the study suggest that SHP099 could be a potential drug target for SHP2-E76K-associated solid tumors and that the dynamic protein-drug interactions could provide insights into the design of more effective SHP2-E76K inhibitors.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as SHP2-E76K is associated with various solid tumors and has become a potential drug target. The study's limitations include the limited number of simulations and the need for further validation of the results. Future research directions could include the development of more effective SHP2-E76K inhibitors based on the dynamic protein-drug interactions identified in this study, as well as the exploration of SHP2-E76K's role in other diseases and the design of novel SHP2-E76K inhibitors with different mechanisms of action.
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