In-SilicoAnalysis of Secondary Metabolites that Modulates Enzymes of Cholesterol Target

Abstract

Hypercholesterolemia has posed a serious threat of heart diseases and stroke worldwide. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid biosynthesis, is regarded as the root of reactive oxygen species (ROS) that generates atherosclerosis and cholesterol crystals. β-Hydroxy β-methylglutaryl-coenzyme A reductase (HMGR) is a rate-limiting enzyme in cholesterol biosynthesis. Although some commercially available enzyme inhibiting drugs have effectively reduced the cholesterol level, most of them have failed to meet the requirements of being apt drug candidates. Here, we have carried out an in-silico analysis of secondary metabolites that have already shown good inhibitory activity against XO and HMGR. Out of 118 secondary metabolites reviewed, sixteen molecules inhibiting XO and HMGR were taken based on IC50 values reported in vitro assays. Further, receptor-based virtual screening was carried out against secondary metabolites using GOLD Protein-Ligand Docking Software, combined with subsequent post-docking, to study the binding affinities of ligands to the enzymes. In-Silico ADMET analysis was carried out to study their pharmacokinetic properties, followed by toxicity prediction through ProTox-II. The molecular docking of amentoflavone (1) (GOLD score 70.54), and ganomycin I (9) (GOLD score 59.61) evinced that the drug has effectively bind at the competitive site of XO and HMGR, respectively. Besides, 6-paradol (3) and selgin (4) could be potential drug candidates to inhibit XO. Likewise, n-octadecanyl-O-α-D-glucopyranosyl(6’→1”)-O-α-D-glucopyranoside (10) could be potential drug candidates to maintain serum cholesterol. In-silico ADMET analysis showed that the sixteen metabolites were optimal within the categorical range in comparison to commercially available XO and HMGR inhibitors, respectively. Toxicity analysis through Protox-II revealed that 6-gingerol (2), ganoleucoin K (11), and ganoleucoin Z (12) are toxic for human use. This computational analysis supports earlier experimental evidence towards the inhibition of XO and HMGR by natural products. Further study is necessary to explore the clinical efficacy of these secondary molecules, which might be alternatives for the treatment of hypercholesterolemia.Graphical abstract

In-vivo hypolipidemic and in-silico HMG-CoA reductase inhibitory effects of 15-Oxoursolic acid from Rhododendron arboreum (Sm)

“…The 3-dimensional structure of HMG-CoA reductase with PDB ID: 1HWK was obtained from the Protein Data Bank (https://www.rcsb.org/search) [43]. The obtained 3D structure of protein was prepared in the Molecular Operating Environment (MOE) 2015.10 for molecular docking [44]. In the preparation process, water molecules were excluded, hydrogen atoms were added, bond orders were carefully corrected, and the ionization states of the receptor protein were correctly determined.…”

In-Vivo Hypolipidemic and In-Silico HMG-CoA Reductase Inhibitory Effects of 15-Oxoursolic Acid from <em>Rhododendron arboreum</em> (Sm)

“…The 3-dimensional structure of HMG-CoA reductase with PDB ID: 1HWK was obtained from the Protein Data Bank (https://www.rcsb.org/search) [38]. The obtained 3D structure of protein was prepared in the Molecular Operating Environment (MOE) 2015.10 for molecular docking [39]. In the preparation process, water molecules were excluded, hydrogen atoms were added, bond orders were carefully corrected, and the ionization states of the receptor protein were correctly determined.…”

Molecular Docking and Dynamics Simulation of Several Flavonoids Predict Cyanidin as an Effective Drug Candidate Against SARS-CoV-2 Spike protein

“…An increasing number of recent studies have used computational methods for identifying new drug targets or drug repurposing candidates. Nowadays, various natural compounds have been repurposed/tested using computer-aided drug discovery programs [12]; [13]. In silico approaches are cost-effective, actionable approaches that can be used to screen several compounds, enabling the discovery of drug combinations and novel drugs.…”