Jukič Marko, Ilaš Janez, Brvar Matjaž, Kikelj Danijel, Cesar Jožko, Anderluh Marko
University of Ljubljana, Faculty of Pharmacy, Department of Medicinal Chemistry, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
National Institute of Chemistry, Laboratory for Biocomputing and Bioinformatics, Hajdrihova ulica 19, 1001 Ljubljana, Slovenia.
Eur J Med Chem. 2017 Jan 5;125:500-514. doi: 10.1016/j.ejmech.2016.09.040. Epub 2016 Sep 16.
Due to increasing emergence of bacterial resistance, compounds with new mechanisms of action are of paramount importance. One of modestly researched therapeutic targets in the field of antibacterial discovery is DNA gyrase B. In the present work we synthesized a focused library of potential DNA gyrase B inhibitors composed of two key pharmacophoric moieties linked by three types of sp-rich linkers to obtain three structural classes of compounds. Using molecular docking, molecular dynamics and analysis of conserved waters in the binding site, we identified a favourable binding mode for piperidin-4-yl and 4-cyclohexyl pyrrole-2-carboxamides while predicting unfavourable interactions with the active site for piperazine pyrrole-2-carboxamides. Biological evaluation of prepared compounds on isolated enzyme DNA gyrase B confirmed our predictions and afforded multiple moderately potent inhibitors of DNA gyrase B. Namely trans-4-(4,5-dibromo-1H-pyrrole-2-carboxamide)cyclohexyl)glycine and 4-(4-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)piperidin-1-yl)-4-oxobutanoic acid with an IC value of 16 and 0.5 μM respectively.
由于细菌耐药性的不断出现，具有新作用机制的化合物至关重要。在抗菌药物研发领域，研究相对较少的治疗靶点之一是DNA促旋酶B。在本研究中，我们合成了一个聚焦文库，其中包含由三种富含sp的连接子连接的两个关键药效基团的潜在DNA促旋酶B抑制剂，以获得三类结构的化合物。通过分子对接、分子动力学以及结合位点中保守水的分析，我们确定了哌啶-4-基和4-环己基吡咯-2-甲酰胺的有利结合模式，同时预测哌嗪吡咯-2-甲酰胺与活性位点存在不利相互作用。对制备的化合物在分离的酶DNA促旋酶B上进行生物学评估，证实了我们的预测，并得到了多种中等效力的DNA促旋酶B抑制剂。具体为反式-4-(4,5-二溴-1H-吡咯-2-甲酰胺基)环己基)甘氨酸和4-(4-(3,4-二氯-5-甲基-1H-吡咯-2-甲酰胺基)哌啶-1-基)-4-氧代丁酸，其IC值分别为16和0.5 μM。
