化学试剂2026，Vol.48Issue(4)：12-19,8.DOI:10.13822/j.cnki.hxsj.2025.0078
醌氧化还原酶1催化三甲基锁醌丙酸还原机制的理论研究
Reduction Mechanism of Trimethylquinone Propionic Acid Catalyzed by Quinone Oxidoreductase 1:A DFT Investigation
摘要
Abstract
Hypoxia-activated prodrugs(HAPs)represent an important therapeutic strategy targeting the hypoxic tumor microenvironment.Trimethyl lock quinone propionic acid(Q3 PA),a quinone-based HAP,can be reduced by quinone oxidoreductase 1(NQO1)under tumor hypoxia,triggering intramolecular cyclization and the release of active pharmacophores.It has been widely employed in the design of antitumor prodrugs and fluorescent probes.However,the specific enzymatic reduction mechanism of Q3PA remains unclear,limiting its further rational optimization.Density functional theory(DFT)and molecular docking methods were employed to systematically investigate the two-electron reduction mechanism of Q3PA mediated by the coenzyme reduced flavin adenine dinucleotide(FADH2)and its interaction mode within the NQO1 active center.By constructing four possible reaction pathways and calculating the structures and energies of each stationary point,the dominant reaction pathway was elucidated:Initially,FADH2 delivered 2e-/1H+to the carbonyl oxygen atom of Q3PA,generating a semiquinone anion intermediate.Subsequently,a histidine residue provided a second proton to form the hydroquinone structure.Finally,intramolecular cyclization yielded a lactone,releasing the pharmacophore.Molecular docking results revealed that the benzoquinone moiety of Q3 PA stacks parallelly above the isoalloxazine ring of FADH2,forming stable π-π interactions.Its carbonyl groups form hydrogen bonds with Tyr126 and Tyr128,while hydrophobic interactions with residues including Pro68,Trp105,Phe106,His161,and Phe178 further ensure precise substrate positioning within the active center.This study elucidated the reduction pathway and key structural features of Q3PA catalyzed by NQO1 at the atomic level,identifies the dominant pathway and rate-determining step,and clarifies the substrate-enzyme recognition mechanism,providing a theoretical basis for the design of novel hypoxia-targeted antitumor drugs.关键词
三甲基锁醌丙酸/还原机制/醌氧化还原酶1/低氧激活/密度泛函理论/分子对接Key words
trimethylquinone propionic acid/reduction mechanism/quinone oxidoreductase 1/hypoxia activation/density functional theory/molecular docking分类
化学化工引用本文复制引用
范文程,任婷,孙国辉,张娜,赵丽娇,钟儒刚..醌氧化还原酶1催化三甲基锁醌丙酸还原机制的理论研究[J].化学试剂,2026,48(4):12-19,8.基金项目
北京市教委北京市重点实验室建设项目(PXM2015_014204_500175). （PXM2015_014204_500175）
