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In silico identification, synthesis and biological evaluation of novel tetrazole inhibitors of MurB
Chemical Biology & Drug Design ( IF 3 ) Pub Date : 2018-02-12 , DOI: 10.1111/cbdd.13172
Martina Hrast 1 , Marko Jukič 1 , Delphine Patin 2 , Julie Tod 3 , Christopher G Dowson 3 , David I Roper 3 , Hélène Barreteau 2 , Stanislav Gobec 1
Affiliation  

In the context of antibacterial drug discovery resurgence, novel therapeutic targets and new compounds with alternative mechanisms of action are of paramount importance. We focused on UDP‐N‐acetylenolpyruvylglucosamine reductase (i.e. MurB), an underexploited target enzyme that is involved in early steps of bacterial peptidoglycan biosynthesis. On the basis of the recently reported crystal structure of MurB in complex with NADP+, a pharmacophore model was generated and used in a virtual screening campaign with combined structure‐based and ligand‐based approaches. To explore chemical space around hit compounds, further similarity search and organic synthesis were employed to obtain several compounds with micromolar IC50 values on MurB. The best inhibitors in the reported series of 5‐substituted tetrazol‐2‐yl acetamides were compounds 13, 26 and 30 with IC50 values of 34, 28 and 25 μm, respectively. None of the reported compounds possessed in vitro antimicrobial activity against Staphylococcus aureus and Escherichia coli.

中文翻译:

MurB新型四唑抑制剂的计算机鉴定、合成和生物学评价

在抗菌药物发现复苏的背景下,新的治疗靶点和具有替代作用机制的新化合物至关重要。我们专注于 UDP- N-乙酰基丙酮基葡糖胺还原酶(即 MurB),这是一种未充分利用的靶酶,参与细菌肽聚糖生物合成的早期步骤。基于最近报道的与 NADP +复合的 MurB 晶体结构,生成了药效团模型,并将其用于结合基于结构和基于配体的方法的虚拟筛选活动。为了探索命中化合物周围的化学空间,进一步的相似性搜索和有机合成被用来获得几种具有微摩尔 IC 50的化合物MurB 上的值。已报道的 5-取代四唑-2-基乙酰胺系列中最好的抑制剂是化合物13、2630,IC 50值分别为 34、28 和25 μm。没有报道的化合物具有体外抗金黄色葡萄球菌大肠杆菌的抗菌活性。
更新日期:2018-02-12
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