Virtual screening, identification and in vitro validation of small molecule GDP-mannose dehydrogenase inhibitors.
Virtual screening, identification and in vitro validation of small molecule GDP-mannose dehydrogenase inhibitors.
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DOI：
10.1039/d3cb00126a
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发表时间：
2023-11-01
影响因子：
4.1
通讯作者：
中科院分区：
文献类型：
--
作者：
在囊性纤维化患者的肺内经历粘液样转化后，病原性细菌铜绿假单胞菌合成大量的毒力因子和胞外多糖藻酸盐。酶鸟苷二磷酸甘露糖脱氢酶（GMD）催化海藻酸盐糖核苷酸结构单元鸟苷二磷酸甘露糖醛酸的限速步骤和不可逆形成。由于人体中没有相应的酶，因此可以阻止其作用机制的策略可以为新的选择性抑制剂打开一条途径，以破坏细菌藻酸盐的生产。使用虚拟筛选，使用Glide、FRED和GOLD算法针对GMD活性位点评价了已知药物空间参数内的1447种化合物的库。使用重组GMD进行的化合物命中评价将40种潜在命中的组细化为6种化合物，其以时间依赖性方式减少NADH产生;其中，松萝酸衍生物表现出比先前建立的糖核苷酸抑制剂强6倍的抑制作用，IC 50值为17 μM。通过共价对接和质谱的进一步分析证实了GMD烷基化的单个位点。铜绿假单胞菌二磷酸鸟苷甘露糖脱氢酶第一个小分子抑制剂的鉴定。
Upon undergoing mucoid conversion within the lungs of cystic fibrosis patients, the pathogenic bacterium Pseudomonas aeruginosa synthesises copious quantities of the virulence factor and exopolysaccharide alginate. The enzyme guanosine diphosphate mannose dehydrogenase (GMD) catalyses the rate-limiting step and irreversible formation of the alginate sugar nucleotide building block, guanosine diphosphate mannuronic acid. Since there is no corresponding enzyme in humans, strategies that could prevent its mechanism of action could open a pathway for new and selective inhibitors to disrupt bacterial alginate production. Using virtual screening, a library of 1447 compounds within the Known Drug Space parameters were evaluated against the GMD active site using the Glide, FRED and GOLD algorithms. Compound hit evaluation with recombinant GMD refined the panel of 40 potential hits to 6 compounds which reduced NADH production in a time-dependent manner; of which, an usnic acid derivative demonstrated inhibition six-fold stronger than a previously established sugar nucleotide inhibitor, with an IC50 value of 17 μM. Further analysis by covalent docking and mass spectrometry confirm a single site of GMD alkylation. Identification of the first small molecule inhibitor for the guanosine diphosphate mannose dehydrogenase from Pseudomonas aeruginosa.
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影响因子：
5.2
作者：
Ahmadipour, Sanaz;Pergolizzi, Giulia;Miller, Gavin J.
通讯作者：
Miller, Gavin J.
影响因子：
6.7
作者：
Bade, Richard;Chan, Ho-Fung;Reynisson, Johannes
通讯作者：
Reynisson, Johannes
影响因子：
3.9
作者：
Kimmel, JL;Tipton, PA
通讯作者：
Tipton, PA
影响因子：
2.8
作者：
TATNELL, PJ;RUSSELL, NJ;GACESA, P
通讯作者：
GACESA, P
影响因子：
5.6
作者：
Zhu, Kai;Bonelli, Kenneth W.;Harder, Edward
通讯作者：
Harder, Edward