Fast Identification of Novel
Lymphoid Tyrosine Phosphatase
Inhibitors Using Target–Ligand Interaction-Based Virtual Screening
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Abstract
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><sub>i</sub> values ranged
from 2.87 to 28.03 μM) and one covalent inhibitor (<i>K</i><sub>i</sub> = 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