Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity.

IF 5.6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Alexia de Matos Czeczot, Mauro Neves Muniz, Marcia Alberton Perelló, Éverton Edésio Dinis Silva, Luís Fernando Saraiva Macedo Timmers, Andresa Berger, Laura Calle Gonzalez, Guilherme Arraché Gonçalves, Sidnei Moura, Pablo Machado, Cristiano Valim Bizarro, Luiz Augusto Basso
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引用次数: 0

Abstract

The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of MtFolB. These compounds exhibited IC50 values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the M. tuberculosis H37Rv strain were evaluated. Compound 3e exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound 3e showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting MtFolB, an attractive molecular target for TB drug development.

与 8-巯基鸟嘌呤相关的结核分枝杆菌二氢蝶呤醛缩酶的晶体结构,以及作为抑制剂的新型 S8 功能化类似物的开发:合成、酶抑制、体外毒性和抗结核活性。
研究人员阐明了结核分枝杆菌 FolB 酶(MtFolB)与其抑制剂 8-巯基鸟嘌呤(8-MG)复合物的晶体结构,其分辨率为 1.95 Å。合成了一系列新型 S8 功能化 8-MG 衍生物,并将其作为 MtFolB 的二氢酮蝶呤醛缩酶(DHNA,EC 4.1.2.25)活性的体外抑制剂进行了评估。这些化合物的 IC50 值在亚摩尔范围内。对五种化合物的活性评估表明了它们的抑制模式和抑制常数。通过分子对接分析确定了复合物形成时酶抑制剂分子间的相互作用和配体构象。评估了所有化合物对结核杆菌 H37Rv 株的抑制活性。化合物 3e 的最低抑制浓度在微摩尔范围内。最后,化合物 3e 对 HepG2 和 Vero 细胞均无明显毒性。本文介绍的研究结果将推动针对 MtFolB 的新型特异性抑制剂的开发,MtFolB 是结核病药物开发的一个极具吸引力的分子靶点。
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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