Interactions of azole-based inhibitors with human heme oxygenase
Interactions of azole-based inhibitors with human heme oxygenase
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唑类抑制剂与人血红素加氧酶的相互作用
DOI：
10.1016/j.jinorgbio.2023.112238
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发表时间：
2023
影响因子：
3.9
通讯作者：
Mak, Piotr J.
中科院分区：
文献类型：
--
作者：
Chiura, Tapiwa;Mitchell, Amanda J.;Grote, Dakota L.;Khojandi, Niloufar;Teague, Ryan M.;Mak, Piotr J.
人血红素加氧酶-1（hHO-1）由于其代谢游离血红素的能力而在人体生理中起着至关重要的作用。血红素降解产物胆绿素和胆红素在细胞中具有保护性抗氧化特性。在癌症的背景下，hHO-1功能赠款癌细胞对标准化疗治疗的防御，从而导致靶向hHO-1的基于唑的抑制剂的开发，用于潜在的抗癌治疗。本工作报告的实验和理论表征的三个唑类抑制剂和hHO-1的活性位点之间的相互作用。结果表明，三种化合物的Kd值均在μM量级。电子吸收和共振拉曼（rR）光谱表明，他们结合到铁血红素和通过氮原子的协调。RR测量揭示了不同的影响抑制剂的几何形状的血红素乙烯基在铁的形式hHO-1。已知外周基团取向的变化会影响血红素氧化还原电位，因此可以反映所研究的唑类的抑制特性。随后的对接研究表明，具有较低Kd值的抑制剂位于接近两个乙烯基，而具有较高Kd值的化合物位于仅一个附近，与RR研究一致。最后，CO加合物的RR研究表明，抑制剂以可逆的方式与血红素结合。总之，结合配体结合研究，UV-Vis和RR光谱，以及计算方法揭示了抑制剂的侧链施加的空间位阻的重要性。
Human heme oxygenase-1 (hHO-1) plays a crucial role in human physiology because of its ability to metabolize free heme. The heme degradation products, biliverdin and bilirubin, were shown to have protective antioxidant properties in cells. In the context of cancer, hHO-1 function grants cancer cells defense from standard chemotherapy treatments, leading to the development of azole-based inhibitors that target hHO-1 for potential anticancer therapy. This work reports experimental and theoretical characterization of interactions between three azole-based inhibitors and the active site of hHO-1. It was found that all three compounds have Kdvalues within the μM order. The electronic absorption and resonance Raman (rR) spectra indicated that they bind to the ferric heme and coordinate through a nitrogen atom. rR measurements revealed varying effects of inhibitors on the geometry of heme vinyl groups in the ferric form of hHO-1. Changes in peripheral group orientation are known to affect heme redox potential, and consequently can reflect the inhibitory properties of studied azoles. The subsequent docking studies showed that inhibitors with lower Kdvalues are located close to two vinyl groups, while the compound with higher Kdis situated near only one, consistent with the rR studies. Finally, the rR studies of the CO adducts showed that the inhibitors bind to the heme in a reversible manner. Altogether, the combination of ligand binding studies, UV–Vis and rR spectroscopies, as well as computational approach revealed an importance of the steric hindrance imposed by the inhibitor's side chain.