Molecular docking of omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to HMGCoA reductase -- the rate limiting enzyme of cholesterol biosynthesis

Abstract Numerous studies show that fish oil components, particularly omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA: C20:5, w-3) and docosahexaenoic acid (DHA: (C22:6, w-3), lower blood cholesterol levels and claim that these PUFAs do this by inhibiting the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR). Statins, a group of commonly prescribed drugs to treat hypercholesterolemia, are also inhibitors of HMGCoAR. Since the intake of EPA and DHA lowers blood cholesterol levels, we used bioinformatics to investigate whether EPA and DHA actually bind to the inhibitor (statin) binding site of the HMGCoAR and thus limit the rise of blood cholesterol. Docking studies with HMGCoAR (1hw9) revealed that both EPA and DHA themselves can bind to the inhibitor binding site with a greater affinity than that of the statin. Therefore, it is concluded that purified EPA and DHA and/or fish oil containing them reduces blood cholesterol levels, at least in part, by directly inhibiting HMGCoAR.