Fast Identification of Novel Lymphoid Tyrosine Phosphatase Inhibitors Using Target–Ligand Interaction-Based Virtual Screening

Lymphoid-specific tyrosine phosphatase (Lyp), a critical signaling regulator of immune cells, is associated with various autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Recent research suggests that Lyp is a potential drug target for autoimmune diseases. Herein, we applied a target–ligand interaction-based virtual screening method to identify novel Lyp inhibitors. Nine Lyp inhibitors with novel scaffolds were identified with eight reversible inhibitors (<i>K</i>_i values ranged from 2.87 to 28.03 μM) and one covalent inhibitor (<i>K</i>_i = 40.98 ± 13.19 μM). The top four compounds (<b>A2</b>, <b>A15</b>, <b>A19</b>, and <b>A26</b>) displayed selectivity over other phosphatases in preliminary experiments, and kinetic analysis indicated that these compounds are competitive inhibitors of Lyp. Compounds <b>A15</b> and <b>A19</b> up-regulated TCR (T cell receptor) mediated signaling and transcriptional activation through inhibition of Lyp activity in T cells. The new chemotypes of Lyp selective inhibitors identified through the target–ligand interaction-based virtual screening may provide new leads for Lyp targeted therapeutic development