Статья

Potential natural inhibitors of xanthine oxidase and HMG-CoA reductase in cholesterol regulation: in silico analysis

Rishab MarahathaCentral Department of Chemistry, Tribhuvan University, Kirtipur, Kathmandu, NepalSaroj BasnetCenter for Drug Design and Molecular Simulation Division, Cancer Care Nepal and Research Center, Jorpati, Kathmandu, NepalBibek Raj BhattaraiCentral Department of Chemistry, Tribhuvan University, Kirtipur, Kathmandu, NepalPrakriti BudhathokiCentral Department of Chemistry, Tribhuvan University, Kirtipur, Kathmandu, NepalBabita AryalCentral Department of Chemistry, Tribhuvan University, Kirtipur, Kathmandu, NepalBikash AdhikariCentral Department of Chemistry, Tribhuvan University, Kirtipur, Kathmandu, NepalGanesh LamichhaneCentral Department of Chemistry, Tribhuvan University, Kirtipur, Kathmandu, NepalDarbin Kumar PoudelCentral Department of Chemistry, Tribhuvan University, Kirtipur, Kathmandu, NepalNiranjan ParajuliCentral Department of Chemistry, Tribhuvan University, Kirtipur, Kathmandu, Nepal. [email protected]

2021en

ABI

Аннотация

BACKGROUND: 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 generate 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 cholesterol levels, most of them have failed to meet potential drug candidates' requirements. Here, we have carried out an in-silico analysis of secondary metabolites that have already shown good inhibitory activity against XO and HMGR in a wet lab setup. METHODS: values reported in 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 explore their pharmacokinetic properties, followed by toxicity prediction through ProTox-II. RESULTS: = - 6.8 Kcal/mol) displayed that the drug has effectively bound at the competitive site of XO and HMGR, respectively. Besides, 6-paradol and selgin could be potential drug candidates inhibiting XO. Likewise, n-octadecanyl-O-α-D-glucopyranosyl (6' → 1″)-O-α-D-glucopyranoside could be potential drug candidates to maintain serum cholesterol. In-silico ADMET analysis has shown that these sixteen metabolites were optimal within the categorical range compared to commercially available XO and HMGR inhibitors, respectively. Toxicity analysis through ProTox-II revealed that 6-gingerol, ganoleucoin K, and ganoleucoin Z are toxic for human use. CONCLUSION: 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.

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Идентификаторы

DOI: 10.1186/s12906-020-03162-5

Цитирования и источники

Цитирований: 2Использованных источников: 0

Показатели — AkademScholar