Abstract：
Multidrug-resistant (MDR) Staphylococcus aureus infections significantly threaten global health. With rising resistance to current antibiotics and limited solutions, the urgent discovery of new, effective, and affordable antibacterials with low toxicity is imperative to combat diverse MDR S. aureus strains. Hence, in this study, we introduce an in silico phytochemical-based approach for discovering novel antibacterial agents, underscoring the potential of computational approaches in therapeutic discovery. Glucomoringin Isothiocyanate (GMG-ITC) from Moringa oleifera Lam. is one of the phytochemical compounds with several biological activities, including antimicrobial, anti-inflammatory, and antioxidant activities, and is also effective against S. aureus. This study focuses on screening GMG-ITC as a potential drug candidate to combat MDR S. aureus infections through a molecular docking approach. Moreover, interaction amino acid analysis, in silico pharmacokinetics, compound target prediction, pathway enrichment analysis and molecular dynamics (MD) simulations were conducted for further investigation. Molecular docking and interaction analysis showed strong binding affinity towards S. aureus lipase, dihydrofolate reductase, and other MDR S. aureus proteins, including penicillin-binding protein 2a, MepR, D-Ala:D-Ala ligase, and RPP TetM, through hydrophilic and hydrophobic interactions. GMG-ITC also showed a strong binding affinity to cyclooxygenase-2 and FAD-dependent NAD(P)H oxidase, suggesting that it is a potential anti-inflammatory and antioxidant candidate that may eliminate inflammation and oxidative stress associated with S. aureus infections. MD simulations validated the stability of the GMG-ITC molecular interactions determined by molecular docking. In silico pharmacokinetic analysis highlights its potency as a drug candidate, showing strong absorption, distribution, and excretion properties in combination with low toxicity. It acts as an active protease and enzyme inhibitor with moderate activity against GPCR ligands, ion channels, nuclear receptor ligands, and kinases. Enrichment analysis further elucidated its involvement in important biological, molecular, and cellular functions with potential therapeutic applications in diseases like cancer, hepatitis B, and influenza. Results suggest that GMG-ITC is an effective antibacterial agent that could treat MDR S. aureus-associated infections.
摘要：
多药耐药(MDR)金黄色葡萄球菌感染严重威胁全球健康。随着对当前抗生素的耐药性上升和解决方案有限，新的紧急发现，有效,低毒性的负担得起的抗菌药物对于对抗多种MDR金黄色葡萄球菌菌株至关重要。因此，在这项研究中，我们介绍了一种基于计算机植物化学的方法来发现新型抗菌剂，强调计算方法在治疗发现中的潜力。来自辣木的葡糖肌醇异硫氰酸酯（GMG-ITC）。是具有多种生物活性的植物化学化合物之一，包括抗菌药物,抗炎,和抗氧化活性，并且对金黄色葡萄球菌也有效。这项研究的重点是筛选GMG-ITC作为一种潜在的候选药物，通过分子对接方法对抗MDR金黄色葡萄球菌感染。此外，相互作用氨基酸分析，计算机药代动力学，复合目标预测，途径富集分析和分子动力学（MD）模拟进行了进一步研究。分子对接和相互作用分析显示了对金黄色葡萄球菌脂肪酶的强结合亲和力，二氢叶酸还原酶，和其他MDR金黄色葡萄球菌蛋白，包括青霉素结合蛋白2a，MepR,D-Ala:D-Ala连接酶,和RPPTetM,通过亲水和疏水相互作用。GMG-ITC还显示出对环氧合酶2和FAD依赖性NAD（P）H氧化酶的强结合亲和力，提示它是一种潜在的抗炎和抗氧化候选物,可以消除与金黄色葡萄球菌感染相关的炎症和氧化应激.MD模拟验证了通过分子对接确定的GMG-ITC分子相互作用的稳定性。计算机药代动力学分析突出了其作为候选药物的效力，表现出强烈的吸收，分布，和排泄特性与低毒性相结合。它作为活性蛋白酶和酶抑制剂，对GPCR配体具有中等活性，离子通道,核受体配体，和激酶。富集分析进一步阐明了其参与重要的生物，分子，和细胞功能在癌症等疾病中具有潜在的治疗应用，乙型肝炎，和流感。结果表明，GMG-ITC是一种有效的抗菌剂，可以治疗MDR金黄色葡萄球菌相关感染。
