In Silico Target Fishing, Molecular Docking, and ADMET Profiling Suggest 6-Shogaol as a Potential Lead Compound Targeting ALOX5 in Insulin Resistance

Abstract

Insulin resistance underlies major metabolic disorders and is driven by chronic low-grade inflammation and oxidative stress that impair insulin signalling in peripheral tissues. Natural compounds with anti-inflammatory and antioxidant activities represent attractive starting points for discovering modulators of this pathological axis, yet the molecular targets mediating their effects often remain unclear. This study employed an integrative in silico strategy combining target fishing, molecular docking, and comprehensive ADMET profiling to explore potential molecular mechanisms of 6-shogaol, a bioactive constituent of Zingiber officinale, in the context of insulin resistance. Target prediction using SwissTargetPrediction nominated arachidonate 5-lipoxygenase (ALOX5) as the highest-probability molecular target of 6-shogaol. Physicochemical and ADMET profiling using SwissADME and ADMETlab 3.0 indicated drug-likeness compliant with Lipinski and Golden Triangle rules, predicted favourable intestinal absorption, and a generally low predicted toxicity profile, while also flagging high cytochrome P450 inhibition, high plasma protein binding, and an ultra-short predicted half-life as liabilities to be considered in future development. Molecular docking against ALOX5 (PDB ID: 6N2W), with redocking validation (RMSD 1.1 Å), showed that 6-shogaol occupies the enzyme active site with a more favourable predicted binding score (–5.67 kJ/mol) than the reference inhibitors zileuton (–5.23 kJ/mol) and masoprocol (–5.08 kJ/mol). These convergent computational findings are consistent with a hypothesis in which 6-shogaol could attenuate leukotriene-mediated inflammatory signalling implicated in insulin resistance. Because the present work is purely computational, the predictions reported here should be interpreted as hypothesis-generating; experimental validation through molecular dynamics simulations, enzymatic ALOX5 inhibition assays, cell-based insulin sensitivity studies, and in vivo models is required before any therapeutic claim can be made. Overall, the integrated analysis supports 6-shogaol as a potential natural lead compound for further experimental investigation in inflammation-associated insulin resistance.