Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase
Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase
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DOI：
10.1101/586255
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发表时间：
2019-03
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通讯作者：
Ricky Cain;R. Salimraj;A. Punekar;D. Bellini;C. Fishwick;L. Czaplewski;D. Scott;G. Harris;C. Dowson;A. Lloyd;D. Roper
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作者：
Ricky Cain;R. Salimraj;A. Punekar;D. Bellini;C. Fishwick;L. Czaplewski;D. Scott;G. Harris;C. Dowson;A. Lloyd;D. Roper
氨酰-tRNA合成酶是蛋白质合成和多种其他代谢过程中普遍存在的必需酶，特别是在细菌物种中。细菌氨酰-tRNA合成酶代表有吸引力的和验证的目标，抗菌药物的发现，如果原核与真核生物的选择性和抗生素耐药性的产生问题可以解决。我们已经确定了大肠杆菌和金黄色葡萄球菌丝氨酰-tRNA合成酶与氨酰腺苷酸类似物复合物的高分辨率X射线晶体结构，并应用基于结构的药物发现方法探索和鉴定了一系列小分子抑制剂，其选择性抑制细菌丝氨酰-tRNA合成酶，与其人类同源物相比，证明了选择性化学抑制这些细菌靶标的途径。
Aminoacyl-tRNA synthetases are ubiquitous and essential enzymes for protein synthesis and also a variety of other metabolic processes, especially in bacterial species. Bacterial aminoacyl-tRNA synthetases represent attractive and validated targets for antimicrobial drug discovery if issues of prokaryotic versus eukaryotic selectivity and antibiotic resistance generation can be addressed. We have determined high resolution X-ray crystal structures of the Escherichia coli and Staphylococcus aureus seryl-tRNA synthetases in complex with aminoacyl adenylate analogues and applied a structure-based drug discovery approach to explore and identify a series of small molecule inhibitors that selectively inhibit bacterial seryl-tRNA synthetases with greater than two orders of magnitude compared to their human homologue, demonstrating a route to selective chemical inhibition of these bacterial targets.