Related Experiment Video
Updated: May 12, 2026
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Discovery of a novel SHP2 allosteric inhibitor using virtual screening, FMO calculation, and molecular dynamic
Zhen Yuan1, Manzhan Zhang1, Longfeng Chang1
1Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China.
Context:
SHP2 is a non-receptor protein tyrosine phosphatase to remove tyrosine phosphorylation. Functionally, SHP2 is an essential bridge to connect numerous oncogenic cell-signaling cascades including RAS-ERK, PI3K-AKT, JAK-STAT, and PD-1/PD-L1 pathways. This study aims to discover novel and potent SHP2 inhibitors using a hierarchical structure-based virtual screening strategy that combines molecular docking and the fragment molecular orbital method (FMO) for calculating binding affinity (referred to as the Dock-FMO protocol). For the SHP2 target, the FMO method prediction has a high correlation between the binding affinity of the protein-ligand interaction and experimental values (R2 = 0.55), demonstrating a significant advantage over the MM/PBSA (R2 = 0.02) and MM/GBSA (R2 = 0.15) methods. Therefore, we employed Dock-FMO virtual screening of ChemDiv database of ∼2,990,000 compounds to identify a novel SHP2 allosteric inhibitor bearing hydroxyimino acetamide scaffold. Experimental validation demonstrated that the new compound (E)-2-(hydroxyimino)-2-phenyl-N-(piperidin-4-ylmethyl)acetamide (7188-0011) effectively inhibited SHP2 in a dose-dependent manner. Molecular dynamics (MD) simulation analysis revealed the binding stability of compound 7188-0011 and the SHP2 protein, along with the key interacting residues in the allosteric binding site. Overall, our work has identified a novel and promising allosteric inhibitor that targets SHP2, providing a new starting point for further optimization to develop more potent inhibitors.
Methods:
All the molecular docking studies were employed to identify potential leads with Maestro v10.1. The protein-ligand binding affinities of potential leads were further predicted by FMO calculations at MP2/6-31G* level using GAMESS v2020 system. MD simulations were carried out with AmberTools18 by applying the FF14SB force field. MD trajectories were analyzed using VMD v1.9.3. MM/GB(PB)SA binding free energy analysis was carried out with the mmpbsa.py tool of AmberTools18. The docking and MD simulation results were visualized through PyMOL v2.5.0.
Insights
Researchers discovered a novel SHP2 allosteric inhibitor using a structure-based virtual screening approach. This new compound shows promise for developing more potent SHP2 inhibitors for cancer therapy.
Area of Science:
- Biochemistry
- Computational Chemistry
- Drug Discovery
Background:
- SHP2 is a crucial non-receptor protein tyrosine phosphatase involved in oncogenic signaling pathways.
- SHP2 acts as a bridge in key cascades like RAS-ERK, PI3K-AKT, JAK-STAT, and PD-1/PD-L1.
- Dysregulation of SHP2 is implicated in various cancers, making it a significant therapeutic target.
Purpose of the Study:
- To identify novel and potent SHP2 inhibitors using a structure-based virtual screening strategy.
- To develop and validate a computational protocol combining molecular docking and Fragment Molecular Orbital (FMO) methods for predicting binding affinity.
- To discover new allosteric inhibitors targeting SHP2.
Main Methods:
- Employed a hierarchical structure-based virtual screening (Dock-FMO protocol) on a large compound database.
- Utilized molecular docking and Fragment Molecular Orbital (FMO) calculations for binding affinity prediction.
- Performed experimental validation, including dose-dependent inhibition assays and molecular dynamics (MD) simulations.
Main Results:
- The Dock-FMO protocol demonstrated high correlation with experimental binding affinities (R²=0.55), outperforming MM/PBSA and MM/GBSA.
- Identified a novel SHP2 allosteric inhibitor with a hydroxyimino acetamide scaffold (compound 7188-0011).
- Compound 7188-0011 exhibited dose-dependent inhibition of SHP2 and stable binding interactions within the allosteric site.
Conclusions:
- The study successfully identified a novel SHP2 allosteric inhibitor using an efficient virtual screening approach.
- The validated Dock-FMO protocol offers a reliable method for discovering protein inhibitors.
- The identified compound serves as a promising starting point for developing next-generation SHP2-targeted cancer therapies.
