Lipogenic stearoyl-CoA desaturase-1 (SCD1) targeted virtual screening for chemical inhibitors: molecular docking / dynamics simulation and in vitro assessment of anti-NAFLD efficacy

Abstract

Amidst rising global prevalence of metabolic syndrome, the associated risk of non-alcoholic fatty liver disease (NAFLD) is also rapidly increasing. The pathogenesis of NAFLD starts with fat accumulation and progresses through inflammation and fibrotic sequel, often involving complex molecular mechanisms involving de novo lipogenesis. Stearoyl-CoA desaturase 1 (SCD1) enzyme, expressed in liver and adipose tissue, converts saturated fatty acids to monounsaturated fatty acids (MUFAs), contributing to triglyceride and cholesterol ester formation. In this study, potential SCD1 inhibitors were screened using the ZINC database of curated medically-approved drugs by virtual screening, molecular docking, and molecular dynamics simulations. The top-scoring five ligands with strong binding affinity against SCD1 were ZINC000003831151 > ZINC000001540998 > ZINC000003830713 > ZINC000000897251 > ZINC000002005305, which showed stable protein-ligand complexation and favorable pharmacokinetic attributes. The top ligand, Montelukast, was experimentally validated for its pharmacological efficacy in an in vitro cell culture model of steatosis (NAFLD). Montelukast showed a dose-dependent decrease in hepatic fat accumulation, reduced levels of free radicals, and lowered oxidative stress (P < 0.05). These outcomes suggest Montelukast to be a potential SCD1 inhibitor, with anti-NAFLD efficacy. These findings open new avenues for therapeutic development of the top 5 ligands in metabolic disorders involving SCD1.