Understanding hypocholesterolemic activity of soy isoflavones: Completing the puzzle through computational simulations

The hypocholesterolemic activity of soy isoflavones has been studied, but the exact mechanism underlying the activity remains unclear. This study reveals the proposed mechanism of the cholesterol-lowering effect of soy isoflavones by computational simulations. Daidzin, Glycitin, Genistin, Daidzein, Glycitein, Genistein, Glyceollin I, Glyceollin II, and Glyceollin III were selected to be analyzed their interaction with 3-Hydroxy-3-Methyl-Glutaryl-Coenzyme A Reductase (HMGCR) and Sterol Regulatory Element-Binding Protein 2 (SREBP2) as key factors in cholesterol biosynthesis as well as Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) as a common target for hypercholesterolemia. Protein-isoflavones interaction was analyzed using AutoDock. According to binding energy calculations, a total of five out of those nine isoflavones, including Glycitin, Genistin, Genistein, Glyceollin II, and Glyceollin III, were favored to be a HMGCR inhibitor but not with SREBP2 and PCSK9. Those isoflavones were then compared with Simvastatin as known inhibitor of HMGCR. Isoflavone with binding energy lower than Simvastatin then directed to molecular dynamics using YASARA and headed into toxicity estimations. Almost all of those isoflavones could bind with HMGCR with better stability than Simvastatin according to molecular dynamics simulations. Toxicity prediction filtered two out of the five isoflavones mentioned earlier as the proper candidate to be an HMGCR inhibitor. Those isoflavones were Genistin and Genistein. In summary, the hypocholesterolemic activity of soy isoflavones may occur by blocking the cholesterol biosynthesis pathway. Communicated by Ramaswamy H. Sarma