Target-Based Virtual and Biochemical Screening Against HMG-CoA Reductase Reveals Allium sativum-Derived Organosulfur Compound N-Acetyl Cysteine as a Cardioprotective Agent

Abstract

In the present study, we evaluate garlic, Allium sativum L., Amaryllidaceae, derived natural organosulfur compounds as effective antioxidant as well as inhibitors of human β-hydroxy-β-methyl-glutaryl-CoA reductase. The initial in silico screening analysis of organosulfur compounds depicted that among all the tested products, N-acetylcysteine, S-ethyl-l-cysteine, alliin, and S-allyl-l-cysteine were among the best commercially available modulators of HMG-R activity (ΔG: − 4.59, − 4.57, − 4.56, and − 4.53 kcal/mol, respectively), when compared to pravastatin (ΔG: − 4.80 kcal/mol). The above-mentioned organosulfur compounds also exhibited an intense DPPH and ABTS radical scavenging potential with the best IC50 observed in N-acetylcysteine, i.e., 7.031 ± 0.51 μM and 5.77 ± 0.22 μM, respectively, which was much better than the IC50 value of ascorbic acid (16.25 ± 0.62 μM and 26.73 ± 0.53 μM, respectively). On the other hand, N-acetylcysteine, S-ethyl-l-cysteine, and alliin exhibited significant in vitro HMG-R inhibitory activity with IC50 of 139.26 ± 1.8 μM, 264.66 ± 5.8 μM, and 292.86 ± 6.8 μM, respectively. Additionally, our enzyme kinetics studies revealed that N-acetylcysteine exhibits competitive inhibition against in vitro β-hydroxy-β-methyl-glutaryl-CoA reductase activity. Based in our in silico and in vitro studies, we concluded that among other selected organosulfur compounds, N-acetylcysteine possesses significant antioxidant potential and competitively inhibits the enzymatic activity of β-hydroxy-β-methyl-glutaryl-CoA. Graphical abstract: [Figure not available: see fulltext.]