LASSBio-1986 as a Multifunctional Antidiabetic Lead: SGLT1/2 Docking, Redox-Inflammatory Modulation and Metabolic Benefits in C57BL/6 Mice
Abstract
Type 2 diabetes mellitus (T2DM) involves chronic hyperglycemia, insulin resistance, low-grade inflammation, and oxidative stress that drive cardiometabolic and renal damage despite current therapies. Sodium-glucose cotransporter (SGLT) inhibitors have reshaped the treatment landscape, but residual risk and safety concerns highlight the need for new agents that combine glucose-lowering efficacy with redox-inflammatory modulation. LASSBio-1986 is a synthetic N-acylhydrazone (NAH) derivative designed as a gliflozin-like scaffold with the potential to interact with SGLT1/2 while also influencing oxidative and inflammatory pathways. Here, we integrated in silico and in vivo approaches to characterize LASSBio-1986 as a multifunctional antidiabetic lead in murine models of glucose dysregulation. PASS and target class prediction suggested a broad activity spectrum and highlighted transporter- and stress-related pathways. Molecular docking indicated high-affinity binding to both SGLT1 and SGLT2, with a modest energetic preference for SGLT2, and ADME/Tox predictions supported favorable oral drug-likeness. In vivo, intraperitoneal LASSBio-1986 improved oral glucose tolerance and reduced glycemic excursions in an acute glucose challenge model in C57BL/6 mice, while enhancing hepatic and skeletal muscle glycogen stores. In a dexamethasone-induced insulin-resistance model, LASSBio-1986 improved insulin sensitivity, favorably modulated serum lipids, attenuated thiobarbituric acid-reactive…
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