利用分子对接和酶动力学评估溴硝醇和双硫仑作为潜在的亚洲韧皮杆菌肌苷 5'-单磷酸脱氢酶抑制剂。
Evaluation of Bronopol and Disulfiram as Potential Liberibacter asiaticus Inosine 5'-Monophosphate Dehydrogenase Inhibitors by Using Molecular Docking and Enzyme Kinetic.
机构信息
College of Horticulture and Forestry, Key Laboratory of Horticultural Plant Biology of Ministry of Education, Huazhong Agricultural University, Wuhan 430070, China.
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China.
出版信息
Molecules. 2020 May 14;25(10):2313. doi: 10.3390/molecules25102313.
Citrus huanglongbing (HLB) is a destructive disease that causes significant damage to many citrus producing areas worldwide. To date, no strategy against this disease has been established. Inosine 5'-monophosphate dehydrogenase (IMPDH) plays crucial roles in the de novo synthesis of guanine nucleotides. This enzyme is used as a potential target to treat bacterial infection. In this study, the crystal structure of a deletion mutant of Las IMPDHΔ98-201 in the apo form was determined. Eight known bioactive compounds were used as ligands for molecular docking. The results showed that bronopol and disulfiram bound to Las IMPDHΔ98-201 with high affinity. These compounds were tested for their inhibition against Las IMPDHΔ98-201 activity. Bronopol and disulfiram showed high inhibition at nanomolar concentrations, and bronopol was found to be the most potent molecule (K = 234 nM). The K value of disulfiram was 616 nM. These results suggest that bronopol and disulfiram can be considered potential candidate agents for the development of Las inhibitors.
黄龙病是一种破坏性疾病，对世界上许多柑橘产区造成了重大损害。迄今为止，尚未建立针对这种疾病的策略。肌苷-5'-单磷酸脱氢酶（IMPDH）在鸟嘌呤核苷酸的从头合成中发挥关键作用。该酶被用作治疗细菌感染的潜在靶标。在这项研究中，确定了 Las IMPDHΔ98-201 缺失突变体在 apo 形式下的晶体结构。使用了八种已知的生物活性化合物作为分子对接的配体。结果表明，溴硝醇和双硫仑与 Las IMPDHΔ98-201 具有高亲和力结合。测试了这些化合物对 Las IMPDHΔ98-201 活性的抑制作用。溴硝醇和双硫仑在纳摩尔浓度下表现出高抑制作用，并且发现溴硝醇是最有效的分子（K = 234 nM）。双硫仑的 K 值为 616 nM。这些结果表明，溴硝醇和双硫仑可以被认为是开发 Las 抑制剂的潜在候选药物。
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