Table 4_Computational analysis of Ayurvedic metabolites for potential treatment of drug-resistant Candida auris.docx

This study explored the effectiveness of secondary metabolites of referred traditional Ayurvedic plants in treating fungal infections, particularly targeting Candida auris. Recognized as a global health threat, this fungus is notorious for its resistance to several antifungal treatments. The inhibition of lanosterol 14α-demethylase causes the depletion of ergosterol, ultimately resulting in the inhibition of fungal cell growth. A total of 469 metabolites, including alkaloids, flavonoids, and tannins from Ayurvedic plants, were screened against CYP51 (PDB ID: 4UYL) using molecular docking. Key active site residues, namely HIS461, CYS463, and TYR122, were targeted to inhibit the ergosterol synthesis, with VNI employed to benchmark the findings. Shortlisted metabolites underwent physicochemical analysis, ADMET analyses, and the principles of medicinal chemistry, which were confirmed through pharmacokinetic simulations. Further, this study investigated the molecular dynamics (MD) of co-crystalized VNI, trans-p-coumaric acid, and MCPHB [(r)-n-(1’-methoxycarbonyl-2’-phenylethyl)-4-hydroxybenzamide] to evaluate RMSD, RMSF, Rg, SASA, cross-correlation of residue motions, PCA, and free energy decomposition. The top compounds demonstrated favorable drug-like criteria. They exhibited good absorption potential with high gastrointestinal uptake. Distribution and metabolism were manageable with low risks of drug-drug interactions. Excretion profiles indicated proper clearance, and toxicity assessments showed low potential for cardiovascular issues. The results showed stable interactions for trans-p-coumaric acid and MCPHB, suggesting that all the ligands maintain stable binding interactions with the protein, which preserves structural integrity across all systems. This comprehensive approach suggests that these natural metabolites from Ayurvedic medicine could potentially serve as primary agents against fungal diseases, pending further validation through controlled in vitro and in vivo clinical trials.

本研究探究了所涉及的阿育吠陀（Ayurvedic）传统药用植物的次生代谢物治疗真菌感染的有效性，尤其针对耳念珠菌（Candida auris）。该真菌被公认为全球健康威胁，因其对多种抗真菌治疗手段产生耐药性而臭名昭著。羊毛甾醇14α-去甲基酶（lanosterol 14α-demethylase）受抑制会导致麦角固醇（ergosterol）耗竭，最终抑制真菌细胞生长。本研究采用分子对接技术，针对细胞色素P450 51（CYP51，PDB编号：4UYL）筛选了来自阿育吠陀药用植物的469种代谢物，涵盖生物碱、黄酮类与鞣质类成分。研究靶向关键活性位点残基组氨酸461（HIS461）、半胱氨酸463（CYS463）与酪氨酸122（TYR122）以抑制麦角固醇合成，并以VNI作为基准参照物对标本次研究结果。经初步筛选得到的候选代谢物依次开展理化性质分析、ADMET（吸收-分布-代谢-排泄-毒性）分析及药物化学成药性评估，并通过药代动力学模拟验证其合理性。此外，本研究针对共结晶的VNI、反式对香豆酸（trans-p-coumaric acid）及MCPHB[(r)-n-(1’-甲氧羰基-2’-苯乙基)-4-羟基苯甲酰胺]开展分子动力学（MD）模拟，评估指标涵盖均方根偏差（RMSD）、均方根波动（RMSF）、回转半径（Rg）、溶剂可及表面积（SASA）、残基运动互相关分析、主成分分析（PCA）及自由能分解。筛选得到的优质化合物表现出优异的类药特性，具备良好的吸收潜力与较高的胃肠道摄取率；其分布与代谢过程可控，药物相互作用风险较低；排泄特征显示其可被正常代谢清除，毒性评估结果表明其引发心血管不良反应的可能性极低。研究结果显示，反式对香豆酸与MCPHB可与靶蛋白形成稳定的相互作用，所有受试配体均能与靶蛋白维持稳定的结合模式，且各体系的蛋白结构完整性得以保持。本研究采用的综合研究策略表明，这些来源于阿育吠陀医学的天然次生代谢物有望成为抗真菌疾病的候选治疗药物，其临床应用价值仍需通过严格的体外（in vitro）与体内（in vivo）临床试验进一步验证。