Biochemical and biophysical research communications · 2026
Integrated discovery of SBLR876: a potent RAGE inhibitor mitigating AGE-RAGE-NF-κB-mediated cytotoxicity and inflammation in diabetic kidney disease.
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Mohammad Al Shahrani Mesfer, Abohassan Mohammad, Dera Ayed A, Vijayaraghavalu Sivakumar, Rajagopalan Prasanna
Аннотация
BACKGROUND AND AIM: Diabetic kidney disease (DKD) is a major microvascular complication characterized by chronic inflammation and fibrosis. The receptor for advanced glycation end products (RAGE) drives these processes via the AGE-RAGE-NF-κB axis. This study aimed to identify and validate novel small-molecule RAGE inhibitors capable of mitigating AGE-driven renal injury.
METHODS: An integrated computational pipeline combining high-throughput virtual screening of the ZINC natural product library, molecular docking, 100-ns molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann surface area (MMPBSA) calculations was employed to identify RAGE modulators. ADMET analyses assessed drug-likeness. The top hit, SBLR876, was experimentally validated using AGE-RAGE binding and in vitro assays in human renal tubular epithelial (HK-2) cells.
RESULTS: SBLR876 exhibited a high docking score (-7.1 kcal/mol), stable MD trajectories (RMSD <0.12 nm), and strong MMPBSA binding energy (-31.42 kcal/mol). ADMET predictions indicated good bioavailability and non-toxicity. In vitro, SBLR876 inhibited AGE-RAGE binding with an IC50 of 282.2 nM, comparable to FPS-ZM1 (93.1 nM). In HK-2 cells, it significantly reduced AGE-induced ROS generation, restored viability, and suppressed IL-6, TNF-α, and MCP-1 secretion, with marked inhibition of NF-κB phosphorylation and nuclear translocation.
CONCLUSION: This integrated computational-experimental approach identifies SBLR876 as a potent RAGE inhibitor that disrupts the AGE-RAGE-NF-κB cascade, offering a promising therapeutic lead for mitigating inflammation and fibrotic progression in diabetic kidney disease.
METHODS: An integrated computational pipeline combining high-throughput virtual screening of the ZINC natural product library, molecular docking, 100-ns molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann surface area (MMPBSA) calculations was employed to identify RAGE modulators. ADMET analyses assessed drug-likeness. The top hit, SBLR876, was experimentally validated using AGE-RAGE binding and in vitro assays in human renal tubular epithelial (HK-2) cells.
RESULTS: SBLR876 exhibited a high docking score (-7.1 kcal/mol), stable MD trajectories (RMSD <0.12 nm), and strong MMPBSA binding energy (-31.42 kcal/mol). ADMET predictions indicated good bioavailability and non-toxicity. In vitro, SBLR876 inhibited AGE-RAGE binding with an IC50 of 282.2 nM, comparable to FPS-ZM1 (93.1 nM). In HK-2 cells, it significantly reduced AGE-induced ROS generation, restored viability, and suppressed IL-6, TNF-α, and MCP-1 secretion, with marked inhibition of NF-κB phosphorylation and nuclear translocation.
CONCLUSION: This integrated computational-experimental approach identifies SBLR876 as a potent RAGE inhibitor that disrupts the AGE-RAGE-NF-κB cascade, offering a promising therapeutic lead for mitigating inflammation and fibrotic progression in diabetic kidney disease.