新德里金属$β$ -内酰胺酶水解头孢氨苄和美罗培南：底物质子化机制为药物依赖性
Hydrolysis of Cephalexin and Meropenem by New Delhi Metallo $β$-Lactamase: Substrate Protonation Mechanism is Drug Dependent
摘要：
由于新德里金属$β$ -内酰胺酶（NDM-1）细菌酶的抗生素耐药性的出现受到极大关注，因为它们能够水解广泛的抗生素。正在努力获得水解机制的原子细节，以开发针对NDM-1的新型药物和抑制剂。特别是，不同抗生素家族的药物分子如何以有效的方式被NDM-1水解仍然是难以捉摸的。在这里，我们报告了NDM-1催化水解头孢氨苄，头孢菌素家族药物，和美罗培南，碳青霉烯家族药物的详细分子机制。本研究采用分子动力学（MD）方法，在密度泛函理论水平上，采用混合量子力学/分子力学（QM/MM）方法，得到了反应路径和自由能。我们发现，开环步骤的机制和自由能垒是相同的药物分子，而随后的质子化步骤不同。特别地，我们观察到质子化步骤的机制取决于药物分子的R2基团。我们的模拟表明，烯丙基碳质子化发生在头孢氨苄药物分子的情况下，其中Lys 211是质子供体和质子转移发生通过水链形成（仅）在开环的中间结构。基于自由能分布，药物水解的整体动力学进行了讨论。最后，我们表明，所提出的机制和自由能分布可以解释各种实验观察。
英文摘要：
Emergence of antibiotic resistance due to New Delhi Metallo $β$-lactamase (NDM-1) bacterial enzymes is of great concern due to their ability to hydrolyze wide range of antibiotics. Efforts are ongoing to obtain the atomistic details of the hydrolysis mechanism in order to develop novel drugs and inhibitors against NDM-1. Especially, it remains elusive how drug molecules of different family of antibiotics are hydrolyzed by NDM-1 in an efficient manner. Here we report the detailed molecular mechanism of NDM-1 catalyzed hydrolysis of cephalexin, a cephalosporin family drug, and meropenem, a carbapenem family drug. This study employs molecular dynamics (MD) simulations using hybrid quantum mechanical/molecular mechanical (QM/MM) methods at the density functional theory level, based on which reaction pathways and the associated free energies are obtained. We find that the mechanism and the free energy barrier for the ring-opening step are the same for both the drug molecules, while the subsequent protonation step differs. In particular, we observe that the mechanism of the protonation step depends on the R2 group of the drug molecule. Our simulations show that allylic carbon protonation occurs in the case of cephalexin drug molecule where Lys211 is the proton donor and the proton transfer occurs via a water chain formed (only) at the ring-opened intermediate structure. Based on the free energy profiles, the overall kinetics of the drug hydrolysis is discussed. Finally, we show that the proposed mechanisms and free energy profiles could explain various experimental observations.
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