Probing the Dynamic Mechanism of Uncommon Allosteric Inhibitors Optimized to Enhance Drug Selectivity of SHP2 with Therapeutic Potential for Cancer Treatment

  • Abdolkarim Farrokhzadeh
  • Farideh Badichi AkherEmail author
  • Mahmoud E. S. SolimanEmail author


There is currently considerable interest in SHP2 as a potential target for treatment of cancer. Mutation in SHP2, particularly the E76A mutation, has been found to seriously confer the phosphatase high activity. Recently, two compounds, 1 and 23, have been reported as potent allosteric inhibitors of both SHP2 wild type (SHP2WT) and the E76A mutant (SHP2E76A), with higher activity than other inhibitors. However, the structural and dynamic implications of their inhibitory mechanisms are yet unexplored which deserve further attention. Herein, the MD simulation applies to gain insight into the atomistic nature of each binding mode of inhibitors 1 and 23 in both SHP2WT and SHP2E76A. The comparative analysis reveals inhibitor 1 can freeze SHP2WT and SHP2E76A in their auto-inhibited conformation better than 23, in agreement with experimental data. GLU250 in both SHP2WT and SHP2E76A and ARG111 and ARG229 in SHP2E76A play a crucial role in the higher activity of 1 compared to 23. The mutation E76A increases the binding affinity of 1 and 23 compared to the wild type, implying that the two inhibitors have been well adopted by the E76A mutant. The findings here can substantially shed light on new strategies for developing novel classes of SHP2 inhibitors with increased potency.


SHP2WT SHP2E76A Phosphatase Allosteric inhibitor Cancer Molecular dynamic simulation 



The authors acknowledge the School of Health Sciences, the University of KwaZulu-Natal, Westville Campus, for financial assistance. They also acknowledge the Centre for High Performance Computing (CHPC,, Cape Town, South Africa, for computational resources. The editorial support of Ms. Carrin Martin, editor for the School of Health Sciences at UKZN, is also acknowledged.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

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ESM 1 (DOCX 25 kb)


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Authors and Affiliations

  1. 1.Molecular Bio-computation and Drug Design Laboratory, School of Health SciencesUniversity of KwaZulu-NatalDurbanSouth Africa

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