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

Author:

Yuan Zhen1,Zhang Manzhan1,Chang Longfeng1,Chen Xingyu1,Ruan Shanshan1,Shi Shanshan1,Zhang Yiqing1,Zhu Lili1,Li Honglin1,Li Shiliang1

Affiliation:

1. East China University of Science & Technology

Abstract

Abstract Investigating the role of protein tyrosine phosphatase SHP2 is a continuing concern in the context of various human diseases, including Noonan syndrome, LEOPARD syndrome, and cancers. 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). 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 7188-0011and 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.

Publisher

Research Square Platform LLC

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