New Delhi metallo-β-lactamase 1 (NDM-1) is an enzyme involved in the drug resistance of many bacteria against most of the widely adopted antibiotics, such as penicillins, cephalosporins, and carbapenems. Consequently, inhibiting NDM-1 swiftly has gained significant interest as a strategy to counteract this bacterial defense mechanism, thereby restoring the effectiveness of antibiotics. Among the inhibitors tested against the enzyme, ebselen (EbSe) showed particularly promising results. This molecule, renowned for its numerous benefits to the human body, targets the enzyme's active site at Cys208 with its selenium atom, facilitating the expulsion of the catalytic zinc ion from the active pocket. Since the inhibitory mechanism of EbSe remains poorly understood, gaining detailed information about it is highly desirable. In the present work, density functional theory calculations and μs-long molecular dynamics simulations are carried out to investigate the reaction mechanism of EbSe with NDM-1, unveiling the structural implications of the inhibition. A large model of the NDM-1 active site is built to investigate the different mechanistic proposals for the SeEbSe-SCys208 bond formation. Deeper insights into Lys211 are also provided to consolidate its role during the inhibition process. Furthermore, the chemical reaction with the ebsulfur (EbS) molecule is also investigated to compare its behavior with that of the periodic relative selenium. Molecular dynamics simulations, besides evidencing the role of the L3 and L10 loops in the occurrence of the inhibition, corroborate the Zn ion release from the active site as a result of the complete disruption of its coordination sphere caused by the creation of the SeEbSe-SCys208 covalent bond.

中文翻译：

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新德里金属-β-内酰胺酶 1 中硫属元-硫属元键形成对抵消抗生素耐药性的作用。


新德里金属-β-内酰胺酶 1 （NDM-1） 是一种酶，参与许多细菌对大多数广泛采用的抗生素（如青霉素、头孢菌素和碳青霉烯类）的耐药性。因此，迅速抑制 NDM-1 作为抵消这种细菌防御机制的策略，从而恢复抗生素的有效性，引起了人们的极大兴趣。在针对该酶测试的抑制剂中，依布硒啉 （EbSe） 显示出特别有希望的结果。这种分子以其对人体的众多益处而闻名，其硒原子靶向酶在 Cys208 的活性位点，促进催化锌离子从活性口袋中排出。由于 EbSe 的抑制机制仍然知之甚少，因此获得有关它的详细信息是非常可取的。在本工作中，进行了密度泛函理论计算和 μs 长分子动力学模拟，以研究 EbSe 与 NDM-1 的反应机理，揭示了抑制的结构意义。构建了 NDM-1 活性位点的大型模型，以研究 SeEbSe-SCys208 键形成的不同机制建议。还提供了对 Lys211 的更深入见解，以巩固其在抑制过程中的作用。此外，还研究了与二硫 （EbS） 分子的化学反应，以将其行为与周期性相对硒的行为进行比较。分子动力学模拟除了证明 L3 和 L10 环在抑制发生中的作用外，还证实了 Zn 离子从活性位点释放，这是由于 SeEbSe-SCys208 共价键的产生导致其配位球完全破坏的结果。