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.

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计算机分析次级代谢产物，可调节胆固醇靶标的酶

高胆固醇血症已经在全世界范围内严重威胁着心脏病和中风。黄嘌呤氧化酶（XO）是尿酸生物合成中的限速酶，被认为是产生动脉粥样硬化和胆固醇晶体的活性氧（ROS）的根源。β-羟基β-甲基戊二酰辅酶A还原酶（HMGR）是胆固醇生物合成中的限速酶。尽管一些可商购的酶抑制药物有效降低了胆固醇水平，但大多数都未能满足成为合适药物候选者的要求。在这里，我们对二级代谢产物进行了计算机分析，这些二级代谢产物已显示出对XO和HMGR的良好抑制活性。在所审查的118种次级代谢产物中，根据体外试验报告的IC50值，选择了16种抑制XO和HMGR的分子。此外，使用GOLD Protein-Ligand Docking软件结合后续的对接进行了针对次生代谢物的基于受体的虚拟筛选，以研究配体与酶的结合亲和力。进行了In-Silico ADMET分析以研究其药代动力学特性，然后通过ProTox-II进行毒性预测。金黄色素（1）（GOLD得分70.54）和高霉素I（9）（GOLD得分59.61）的分子对接表明，该药物分别在XO和HMGR的竞争位点有效结合。此外，6-paradol（3）和selgin（4）可能是抑制XO的潜在药物。同样，正十八烷基-O-α-D-吡喃葡萄糖苷（6→1）-O-α-D-吡喃葡萄糖苷（10）可能是维持血清胆固醇的潜在药物。硅上ADMET分析表明，与商用XO和HMGR抑制剂相比，十六种代谢物在分类范围内最佳。通过Protox-II进行的毒性分析表明，6-姜油酚（2），甘露糖苷K（11）和甘露糖苷Z（12）对人体有毒。这种计算分析为天然产物抑制XO和HMGR提供了较早的实验证据。有必要进行进一步的研究以探索这些次级分子的临床功效，这可能是治疗高胆固醇血症的替代方法。这种计算分析为天然产物抑制XO和HMGR提供了较早的实验证据。有必要进行进一步的研究以探索这些次级分子的临床疗效，这可能是治疗高胆固醇血症的替代方法。这种计算分析为天然产物抑制XO和HMGR提供了较早的实验证据。有必要进行进一步的研究以探索这些次级分子的临床疗效，这可能是治疗高胆固醇血症的替代方法。