Deciphering Potent Protein Tyrosine Phosphatase-1B Inhibitors Through In silico Molecular Docking, MMGBSA, and Molecular Dynamics

Abstract

Alzheimer's disease (AD) stands as the most prevalent progressive neurodegenerative disorder, marked by cognitive impairment, memory loss, and cognitive deficits. In the present study, the targeted protein tyrosine phosphatase 1B (PTP1B), a crucial enzyme involved in various signaling pathways, is associated with AD pathogenesis. Our study employs the virtual screening of the compounds from an extensive database. Based on the docking score, the molecular dynamics simulation has been performed for top three compounds, donepezil and ertiprotafib for the comparative study of the molecules. As a result, the molecules CNP0377119, CNP0390654, CNP0377195, donepezil, and ertiprotafib were identified with the favorable docking scores. Further analyses, including PRIME MMGB-SA and ADMET properties, focused on standard amino acids like Asp193 and Glu276. In the 100 ns molecular simulation trajectory, the three compounds exhibited stability through effective binding properties with ligands. These interactions included favorable binding conformations and hydrogen bond formations with Asn193, Glu276, Lys197, Glu200, and Tyr46. The π-π stacking interactions were also observed with amino acids Phe196 and Phe280. The allosteric inhibitor of PTP1B directly attaches to the WPD loop when the cysteine-phosphate intermediate is in its open conformation hindering the closure of the WPD loop, thereby inhibiting the PTP1B activity.