PurposeProtein tyrosine phosphatases (PTPs) play an essential way in diseases including cancer, obesity, diabetes and autoimmune disorders. As a member of PTPs, low molecular weight PTP (LMPTP) has been a well-recognized anti-insulin resistance target in obesity. However, the number of reported LMPTP inhibitors is limited. Our research aims to discover a novel LMPTP inhibitor and evaluate its biological activity against insulin resistance.MethodsA virtual screening pipeline based on the X-ray co-crystal complex of LMPTP was constructed. Enzyme inhibition assay and cellular bioassay were used to evaluate the activity of screened compounds.ResultsThe screening pipeline rendered 15 potential hits from Specs chemical library. Enzyme inhibition assay identified compound F9 (AN-465/41163730) as a potential LMPTP inhibitor with a K i value of 21.5 ± 7.3 μM. Cellular bioassay showed F9 could effectively increase the glucose consumption of HepG2 cells as a result of releasing insulin resistance by regulating PI3K-Akt pathway.ConclusionIn summary, this study presents a versatile virtual screening pipeline for potential LMPTP inhibitor discovery and provides a novel-scaffold lead compound that is worthy of further modification to get more potent LMPTP inhibitors.