Computational Characterization of the Inhibition Mechanism of Xanthine Oxidoreductase by Topiroxostat.
Computational Characterization of the Inhibition Mechanism of Xanthine Oxidoreductase by Topiroxostat.
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DOI：
10.1021/acscatal.3c01245
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发表时间：
2023-04
期刊：
影响因子：
12.9
通讯作者：
Yazdan Maghsoud;Chao Dong;G. Cisneros
中科院分区：
文献类型：
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作者：
Yazdan Maghsoud;Chao Dong;G. Cisneros
黄嘌呤氧化酶（XO）是含蝶呤的酶家族的成员。它将黄嘌呤转化为尿酸，作为人体内嘌呤代谢的最后一步。血液中尿酸浓度高直接导致痛风和高尿酸血症等人类疾病。因此，多年来，临床上一直使用抑制人XO生物合成尿酸的药物来降低血液中尿酸的浓度。本研究采用分子动力学（MD）和量子力学/分子力学（QM/MM）计算方法，对XO和一种新的有前途的药物托吡司他（代号：FYX-051）的抑制机制进行了研究。据报道，该药物可作为非共价和共价抑制剂，并通过其所有羟基化代谢产物（包括2-羟基-FYX-051、二羟基-FYX-051和三羟基-FYX-051）进行逐步抑制。然而，每种代谢物的详细抑制机制仍然难以捉摸，可以用于设计具有类似抑制功能的更有效的药物。因此，在本文中，我们提出了FYX-051的结构和动力学效应的计算研究和计算的反应机制，所有的氧化步骤催化的活性位点中的异蝶呤中心。每种代谢产物的抑制反应在酶的活性位点，结合亲和力，和与周围的氨基酸残基的非共价相互作用的拟议的反应机制的计算结果与以前报道的实验结果是一致的。通过能量分解分析（EDA）和非共价相互作用（NCI）技术对非共价相互作用的分析表明，残基L 648、K771、E802、R839、L 873、R880、R912、F914、F1009、L1014和A1079可以用作进一步开发混合型抑制剂的关键相互作用残基。
Xanthine oxidase (XO) is a member of the molybdopterin-containing enzyme family. It interconverts xanthine to uric acid as the last step of purine catabolism in the human body. The high uric acid concentration in the blood directly leads to human diseases like gout and hyperuricemia. Therefore, drugs that inhibit the biosynthesis of uric acid by human XO have been clinically used for many years to decrease the concentration of uric acid in the blood. In this study, the inhibition mechanism of XO and a new promising drug, topiroxostat (code: FYX-051), is investigated by employing molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations. This drug has been reported to act as both a noncovalent and covalent inhibitor and undergoes a stepwise inhibition by all its hydroxylated metabolites, which include 2-hydroxy-FYX-051, dihydroxy-FYX-051, and trihydroxy-FYX-051. However, the detailed mechanism of inhibition of each metabolite remains elusive and can be useful for designing more effective drugs with similar inhibition functions. Hence, herein we present the computational investigation of the structural and dynamical effects of FYX-051 and the calculated reaction mechanism for all of the oxidation steps catalyzed by the molybdopterin center in the active site. Calculated results for the proposed reaction mechanisms for each metabolite's inhibition reaction in the enzyme's active site, binding affinities, and the noncovalent interactions with the surrounding amino acid residues are consistent with previously reported experimental findings. Analysis of the noncovalent interactions via energy decomposition analysis (EDA) and noncovalent interaction (NCI) techniques suggests that residues L648, K771, E802, R839, L873, R880, R912, F914, F1009, L1014, and A1079 can be used as key interacting residues for further hybrid-type inhibitor development.