Identification of a New Class of FtsZ Inhibitors by Structure-Based Design and in Vitro Screening
Identification of a New Class of FtsZ Inhibitors by Structure-Based Design and in Vitro Screening
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DOI：
10.1021/ci400203f
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发表时间：
2013-08-01
影响因子：
5.6
通讯作者：
Wong, Kwok-Yin
中科院分区：
文献类型：
--
作者：
Chan, Fung-Yi;Sun, Ning;Wong, Kwok-Yin
丝状温度敏感突变体Z（FtsZ）是细菌细胞分裂中的必需GT3，在革兰氏阳性和革兰氏阴性细菌中高度保守，因此被认为是治疗耐药细菌感染的有吸引力的靶标。在这项研究中，一类新的FtsZ抑制剂轴承的嘧啶-奎宁环骨架，确定了基于结构的虚拟筛选的天然产物库。迭代轮的计算机模拟研究和生物学评价建立了新化合物的初步结构活性关系。有效的FtsZ抑制剂，具有低微摩尔IC 50和对S. aureus和E.这些发现支持使用虚拟筛选和基于结构的设计来合理开发具有创新作用机制的新型抗菌剂。
The Filamenting temperature-sensitive mutant Z (FtsZ), an essential GTPase in bacterial cell division, is highly conserved among Gram-positive and Gram-negative bacteria and thus considered an attractive target to treat antibiotic-resistant bacterial infections. In this study, a new class of FtsZ inhibitors bearing the pyrimidine-quinuclidine scaffold was identified from structure-based virtual screening of natural product libraries. Iterative rounds of in silico studies and biological evaluation established the preliminary structure activity relationships of the new compounds. Potent FtsZ inhibitors with low micromolar IC50 and antibacterial activity against S. aureus and E. coli were found. These findings support the use of virtual screening and structure-based design for the rational development of new antibacterial agents with innovative mechanisms of action.