Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Al-Quwayiyah 19257, Riyadh, Saudi Arabia.
Int J Biol Macromol. 2024 Nov;279(Pt 3):135459. doi: 10.1016/j.ijbiomac.2024.135459. Epub 2024 Sep 7.
Staphylococcus aureus (S. aureus), commonly found on the skin and nose, causes minor skin conditions to life-threatening diseases, including boils or impetigo, pneumonia, and bloodstream infections. MRSA (Methicillin-Resistant S. aureus) is a strain resistant to many antibiotics and poses a significant challenge in clinical settings. Nowadays, the alternative drug Linezolid is used, and it is not clear when MRSA starts resistance to it, necessitating the need for more alternative drugs with the least chance of developing resistance. This study aims to identify a multitargeted drug candidate with better efficacy than Linezolid. We have taken three hydrolase and transferase proteins from S. aureus, performed the multitargeted docking studies with human-approved drugs, and compared them with the control drug Linezolid. The docking and MM\GBSA scores ranging from -6.79 to -5.78 Kcal/mol and - 37.47 to 30.16 Kcal/mol, respectively, that revealed Deprodone (used for inflammatory skin disorders, bowel disease, and fatty acid metabolism disorders) can be a far better and multitargeted drug candidate than Linezolid. We extended our studies to include extensive pharmacokinetics and molecular interaction fingerprints for interaction pattern studies. Also, the DFT computations optimised the drug, and we extended our studies for MD Simulation in water for 100 ns, which showed the complexes among the identified drug with proteins are entirely stable with acceptable deviation, fluctuations and many intermolecular interactions that make them stable. We also performed the MM\GBSA studies on MD simulation's all 1000 frames to understand the complex energy level. All the results reveal promising interactions between Deprodone and the targeted enzymes, suggesting its potential as a multitargeted therapeutic agent-however, experimental studies need to validate Deprodone against MRSA.
金黄色葡萄球菌（S. aureus）通常存在于皮肤和鼻子上，可引起从轻微皮肤问题到危及生命的疾病，包括疖子或脓疱疮、肺炎和血液感染。耐甲氧西林金黄色葡萄球菌（MRSA）是一种对许多抗生素具有耐药性的菌株，在临床环境中构成重大挑战。如今，使用替代药物利奈唑胺，但尚不清楚 MRSA何时开始对其产生耐药性，因此需要更多具有最低耐药风险的替代药物。本研究旨在寻找一种比利奈唑胺疗效更好的多靶标药物候选物。我们从金黄色葡萄球菌中提取了三种水解酶和转移酶蛋白，对其进行了多靶标对接研究，并与对照药物利奈唑胺进行了比较。对接和 MM\GBSA 评分分别为-6.79 至-5.78 Kcal/mol 和-37.47 至 30.16 Kcal/mol，表明 Deprodone（用于治疗炎症性皮肤疾病、肠道疾病和脂肪酸代谢紊乱）可能是一种比利奈唑胺更好的多靶标药物候选物。我们将研究扩展到包括广泛的药代动力学和分子相互作用指纹图谱，以进行相互作用模式研究。此外，DFT 计算优化了药物，我们将研究扩展到在水中进行 100 ns 的 MD 模拟，结果表明所鉴定的药物与蛋白质之间的复合物完全稳定，具有可接受的偏差、波动和许多使它们稳定的分子间相互作用。我们还对 MD 模拟的所有 1000 个帧进行了 MM\GBSA 研究，以了解复合物的能量水平。所有结果均表明 Deprodone 与靶标酶之间存在有前途的相互作用，表明其作为多靶标治疗剂的潜力-然而，需要进行实验研究来验证 Deprodone 对 MRSA 的作用。
