| 史祥睿,代宇婕,张弢,张庆华,刘威.化学通报,2021,84(11):1237-1242. |
| 基于分子对接的thanatin与NDM-1分子动力学模拟研究 |
| Molecular dynamics simulation study of thanatin and NDM-1 based on molecular docking |
| 投稿时间：2021-03-30 修订日期：2021-04-27 |
| DOI： |
| 中文关键词: NDM-1 thanatin 分子对接 动力学模拟 活性 |
| 英文关键词:NDM-1, thanatin, Molecular docking, Molecular dynamics simulation, Activity |
| 基金项目:陆军军医大学临床技术创新培育项目(CX2019LC118)资助 |
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| 中文摘要: |
| 耐碳青霉烯类抗生素的超级细菌给人类健康带来了严重威胁，其所携带的金属 β-内酰胺酶编码基因是耐药性的主要来源。NDM-1作为其中传播最广、活性最强的 β-内酰胺酶，其抑制剂的研发刻不容缓。具有广谱作用的抗菌肽thanatin对NDM-1展现出了较好的抑制效果，但抑制机理并不清楚。本文使用HPEPDOCK与Rosetta FlexPepDock服务器，将thanatin与NDM-1进行了分子对接，并使用Desmond软件包对对接模型进行了分子动力学模拟。结果表明，thanatin与NDM-1活性中心的Zn2+ 并无直接相互作用，而作为竞争性抑制剂结合于NDM-1的活性口袋，阻止抗生素分子进入活性口袋与Zn2+ 结合，从而抑制NDM-1的水解活性。本文为研发有效的NDM临床抑制剂探索了可行的方法。 |
| 英文摘要: |
| The carbapenem-resistant bacteria has posed serious threats to human health. This resistance mostly stems from plasmid-carried genes encoding metallo-β-lactamases (MBLs). As the most widespread MBL, NDM-1 shows highest activity of β-lactam hydrolysis and thus has become a hotspot for inhibitors development during the latest decades. Thanatin, a broad-spectrum antimicrobial peptide displays good inhibition efficacy against NDM-1, but the mechanism is unknown. In this paper, we conducted molecular docking of thanatin to NDM-1 using the HPEPDOCK sever and the Rosetta FlexPepDock sever, followed by molecular dynamics simulation using the Desmond suite. Based on the analyses of the docked models and the MD trajectory, the results obtained from our calculation suggest that thanatin not interact directly with Zn2+ in the active center of NDM-1, but acts as a competitive inhibitor binding to the active pocket of NDM-1, thereby preventing the binding of an antibiotic substrate to the Zn2+ and inhibiting the hydrolytic activity of NDM-1. Our study may help researchers to find a feasible way to develop clinically efficient inhibitors of NDMs. |
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