Identification of novel PTP1B inhibitor for the treatment of LPS-induced myocardial apoptosis: machine learning based virtual screening and biological evaluation

Sepsis-induced cardiovascular dysfunction (SICD) poses a serious threat to human life. Protein tyrosine phosphatase 1B (PTP1B) displays an essential role in SICD occurrence, so discovering novel inhibitors targeting PTP1B is an effective strategy for SICD treatment. In this research, we exploited a novel virtual screening pipeline consisting of both ligand-based and structure-based modules to find novel PTP1B inhibitors, and compound PI-2 with IC₅₀ = 4.1 ± 0.3 μM was successfully discovered. Enzymatic and cellular thermal shift assay showed PI-2 displayed a moderate PTP1B inhibitory activity and a good selectivity towards both PTP1B and TCPTP. Besides, PI-2 effectively protected Lipopolysaccharide (LPS) induced AC16 injury by reducing cell ROS levels and enhancing mitochondrial membrane potential. Overall, this research not only provides a novel virtual screening strategy for discovering novel PTP1B inhibitors, but also supplies a potential candidate for further optimisation for the treatment of SICD.