Ferroptosis is a recently discovered iron-dependent form of non-apoptotic cell death caused by the accumulation of membrane lipid peroxidation products, which is involved in various pathological conditions of the brain, kidney, liver and heart. A potent spiroquinoxalinamine derivative named liproxstatin-1 is discovered by high-throughput screening, which is able to suppress ferroptosis via lipid peroxide scavenging in vivo. Thus, molecular simulations, density functional theory (DFT) and variational transition-state theory with a small-curvature tunneling (SCT) coefficient are utilized to elucidate the detailed mechanisms of inactivation of a lipid peroxide radical by liproxstatin-1. H-atom abstracted from liproxstatin-1 by a CH₃OO˙ radical occurs preferentially at the aromatic amine site (1′-NH) under thermodynamic and frontier molecular orbital analysis. The value of a calculated rate constant at 300 K is up to 6.38 × 10³ M⁻¹ S⁻¹, indicating that the quantum tunneling effect is responsible for making a free radical trapping reaction more efficient by liproxstatin-1. The production of a liproxstatin-1 radical is easily regenerated to the active reduced form by ubiquinol in the body to avoid secondary damage by free radicals. A benzene ring and the higher HOMO energy are beneficial to enhance the lipid radical scavenging activity based on the structure–activity relationship study. Overall, the present results provide theoretical insights into the exploration of novel ferroptosis inhibitors.

中文翻译：

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通过脂环抑素-1灭活脂质过氧化物自由基来抑制肥大作用机制的理论见解

Ferroptosis是最近发现的铁依赖性形式的非凋亡性细胞死亡，它是由膜脂质过氧化产物的积累引起的，膜脂质过氧化产物的积累涉及脑，肾，肝和心脏的各种病理状况。通过高通量筛选发现了一种名为liproxstatin-1的强效螺喹喔啉胺衍生物，该衍生物能够通过体内脂质过氧化物清除来抑制肥大症。因此，利用分子模拟，密度泛函理论（DFT）和具有小曲率隧穿（SCT）系数的变迁过渡态理论来阐明脂环素1灭活脂质过氧化物自由基的详细机理。通过CH ₃从liproxstatin-1中提取H原子在热力学和前沿分子轨道分析下，OO +基团优先出现在芳族胺位点（1'-NH）。在300 K处计算出的速率常数的值最高为6.38×10 ³ M ^-1 S ^-1，表明量子隧穿效应负责使liproxstatin-1更加有效地进行自由基捕获反应。liproxstatin-1自由基的产生很容易在体内被泛醇再生为活性的还原形式，从而避免了自由基的继发性破坏。根据结构-活性关系研究，苯环和较高的HOMO能量有助于增强脂质自由基清除活性。总的来说，目前的结果为新型铁氧体病抑制剂的探索提供了理论上的见识。