Discovery of Novel Allosteric SHP2 Inhibitor Using Pharmacophore-Based Virtual Screening, Molecular Docking, Molecular Dynamics Simulation, and Principal Component Analysis

SHP2 belongs to a cytoplasmic non-receptor protein tyrosine phosphatase class. It plays a critical role in the development of various cancers, such as gastric cancer, leukemia, and breast cancer. Thus, SHP2 has gained the interest of researchers as a potential target for inhibiting tumor cell proliferation in SHP2-dependent cancers. This study employed pharmacophore-based virtual screening, molecular docking, molecular dynamic (MD) simulations, MM/PBSA, and principal component analysis (PCA), followed by ADME prediction. We selected three potential hits from a collective database of more than one million chemical compounds. The stability of these selected hit-protein complexes was analyzed using 500 ns MD simulations and binding free energy calculations. The identified hits Lig₁, Lig₆, and Lig₁4 demonstrated binding free energies of -161. 49 kJ/mol, -151. 28 kJ/mol, and -107. 13 kJ/mol, respectively, compared to the reference molecule (SHP099) with a ΔG of -71. 48 kJ/mol. Our results showed that the identified compounds could be used as promising candidates for selective SHP2 allosteric inhibition in cancer.