QM/MM 建模研究 A 类β-内酰胺酶揭示了氨苄西林和头孢氨苄的不同酰化途径。
QM/MM modeling of class A β-lactamases reveals distinct acylation pathways for ampicillin and cefalexin.
机构信息
Department of Chemistry, Center for Research Computing, Center for Drug Discovery, Design, and Delivery (CD4), Southern Methodist University, Dallas, Texas 75205, USA.
The Verna and Marrs McLean Department of Biochemistry and Molecular Biology and Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
出版信息
Org Biomol Chem. 2021 Nov 3;19(42):9182-9189. doi: 10.1039/d1ob01593a.
Efficient mechanism-based design of antibiotics that are not susceptible to β-lactamases is hindered by the lack of comprehensive knowledge on the energetic landscapes for the hydrolysis of various β-lactams. Herein, we adopted efficient quantum mechanics/molecular mechanics simulations to explore the acylation reaction catalyzed by CTX-M-44 (Toho-1) β-lactamase. We show that the catalytic pathways for β-lactam hydrolysis are correlated to substrate scaffolds: using Glu166 as the only general base for acylation is viable for ampicillin but prohibitive for cefalexin. The present computational workflow provides quantitative insights to facilitate the optimization of future β-lactam antibiotics.
高效的、基于机制的抗生素设计不会受到β-内酰胺酶影响，但由于缺乏对各种β-内酰胺水解的能量景观的全面了解，这一目标受到了阻碍。在此，我们采用高效的量子力学/分子力学模拟来探索 CTX-M-44（Toho-1）β-内酰胺酶催化的酰化反应。我们表明，β-内酰胺水解的催化途径与底物支架相关：使用 Glu166 作为唯一的酰化通用碱对于氨苄西林是可行的，但对于头孢氨苄则是不可行的。本计算工作流程提供了定量的见解，有助于优化未来的β-内酰胺抗生素。
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