Discovery of a novel SHP2 allosteric inhibitor using virtual screening, FMO calculation, and molecular dynamic simulation

  • J Mol Model. 2024 Apr 13;30(5):131. doi: 10.1007/s00894-024-05935-y.
Zhen Yuan  #  1 ,  Manzhan Zhang  #  1 ,  Longfeng Chang  #  1 ,  Xingyu Chen  1 ,  Shanshan Ruan  1 ,  Shanshan Shi  1 ,  Yiqing Zhang  1 ,  Lili Zhu  2 ,  Honglin Li  3  4  5 ,  Shiliang Li  6  7
Affiliations
  • 1. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China.
  • 2. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China. [email protected].
  • 3. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China. [email protected].
  • 4. Innovation Center for AI and Drug Discovery, East China Normal University, Shanghai, 200062, China. [email protected].
  • 5. Lingang Laboratory, Shanghai, 200031, China. [email protected].
  • 6. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai, China. [email protected].
  • 7. Innovation Center for AI and Drug Discovery, East China Normal University, Shanghai, 200062, China. [email protected].
  • # Contributed equally.
PMID: 38613643 DOI: 10.1007/s00894-024-05935-y
Abstract

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.

Keywords
Allosteric inhibitor; Fragment molecular orbital method; Molecular dynamics simulation; SHP2; Virtual screening.
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