Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
J Biomol Struct Dyn. 2022 Jun;40(9):4188-4196. doi: 10.1080/07391102.2020.1854118. Epub 2020 Dec 7.
The oxidation process, catalyzed by the peroxidase enzymes, occurs in all domains of life to detoxify the hydrogen peroxide toxicity. The most well-known, applicable and vastly studied member of the peroxidases family is horseradish peroxidase (HRP), especially the isoenzyme C (HRP C). HRP (primarily HRP C) is commercially available and applicable in biotechnology and diagnosis. Recently, a novel application of HRP has been introduced in cancer therapy as the combination of HRP with indole-3-acetic acid (IAA). The anticancer activity of HRP/IAA complex is through oxidation of IAA by HRP in hypoxic tumor condition, which leads to apoptosis and cancerous cell death. However, the molecular interaction of HRP/IAA has not been elucidated. Identifying the interaction of IAA with HRP would provide a better insight into its function and applications. In this study, molecular docking and molecular dynamics (MD) simulation were applied to determine the molecular interaction of the IAA/HRP complex. The docking study represented that IAA bound at the 'exposed' heme edge of the HRP enzyme, and the IAA entrance to the enzyme was situated at the carboxymethyl side-chain of the selected structure. Our computational results showed the HRP/IAA complex structure stability. While hydrogen bond formation with ARG38 and HIS42 stabilized the substrate, hydrophobic interactions with Phe68, Gly69, Leu138, Pro139, Pro141 and Phe179 contributed to IAA/HRP complex stability. The results can help to better understand peroxidase enzyme activity and would pave the way for future development of new therapeutics with improved anticancer efficacy.Communicated by Ramaswamy H. Sarma.
氧化过程是在所有生命领域中发生的，由过氧化物酶催化，以解毒过氧化氢的毒性。过氧化物酶家族中最著名、最适用和研究最多的成员是辣根过氧化物酶（HRP），特别是同工酶 C（HRP C）。HRP（主要是 HRP C）可商业获得，并可应用于生物技术和诊断。最近，HRP 的一个新应用在癌症治疗中被引入，即 HRP 与吲哚-3-乙酸（IAA）的结合。HRP/IAA 复合物的抗癌活性是通过 HRP 在缺氧肿瘤条件下氧化 IAA 引起的，导致细胞凋亡和癌细胞死亡。然而，HRP/IAA 的分子相互作用尚未阐明。确定 IAA 与 HRP 的相互作用将提供对其功能和应用的更好理解。在这项研究中，应用分子对接和分子动力学（MD）模拟来确定 IAA/HRP 复合物的分子相互作用。对接研究表明，IAA 结合在 HRP 酶的“暴露”血红素边缘，酶的 IAA 入口位于所选结构的羧甲基侧链上。我们的计算结果表明 HRP/IAA 复合物结构稳定。与 ARG38 和 HIS42 形成氢键稳定了底物，而与 Phe68、Gly69、Leu138、Pro139、Pro141 和 Phe179 的疏水相互作用有助于 IAA/HRP 复合物的稳定性。这些结果有助于更好地理解过氧化物酶的酶活性，并为未来开发具有提高抗癌疗效的新疗法铺平道路。由 Ramaswamy H. Sarma 传达。
