Department of Chemistry, Box 870336, University of Alabama, Tuscaloosa, AL 35487-0336, United States of America.
Department of Chemistry, Box 870336, University of Alabama, Tuscaloosa, AL 35487-0336, United States of America.
J Inorg Biochem. 2020 Apr;205:110994. doi: 10.1016/j.jinorgbio.2020.110994. Epub 2020 Jan 13.
The Mycobacterium tuberculosis (Mtb) genome encodes 20 different cytochrome P450 enzymes (CYPs), many of which serve essential biosynthetic roles. CYP51B1, the Mtb version of eukaryotic sterol demethylase, remains a potential therapeutic target. The binding of three drug fragments containing nitrogen heterocycles to CYP51B1 is studied here by continuous wave (CW) and pulsed electron paramagnetic resonance (EPR) techniques to determine how each drug fragment binds to the heme active-site. All three drug fragments form a mixture of complexes, some of which retain the axial water ligand from the resting state. Hyperfine sublevel correlation spectroscopy (HYSCORE) and electron-nuclear double resonance spectroscopy (ENDOR) observe protons of the axial water and on the drug fragments that reveal drug binding modes. Binding in CYP51B1 is complicated by the presence of multiple binding modes that coexist in the same solution. These results aid our understanding of CYP-inhibitor interactions and will help guide future inhibitor design.
结核分枝杆菌（Mtb）基因组编码 20 种不同的细胞色素 P450 酶（CYPs），其中许多酶具有重要的生物合成作用。Mtb 版本的真核固醇脱甲基酶 CYP51B1 仍然是一个潜在的治疗靶点。本研究通过连续波（CW）和脉冲电子顺磁共振（EPR）技术研究了含有氮杂环的三个药物片段与 CYP51B1 的结合，以确定每个药物片段如何与血红素活性位点结合。所有三种药物片段都形成了混合物的复合物，其中一些保留了来自静息状态的轴向水配体。超精细亚层相关谱（HYSCORE）和电子-核双共振谱（ENDOR）观察到轴向水和药物片段上的质子，揭示了药物结合模式。CYP51B1 中的结合由于存在多种结合模式而变得复杂，这些模式在同一溶液中共存。这些结果有助于我们理解 CYP 抑制剂相互作用，并将有助于指导未来抑制剂的设计。
