Impact of IDH Mutations on Ligand Unbinding: Insights from Steered Molecular Dynamics.

IF 3.3 4区 医学 Q3 CHEMISTRY, MEDICINAL
Alka Singh, Sonia Kumari, M Elizabeth Sobhia
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引用次数: 0

Abstract

Aim: This study explores the unbinding dynamics of alpha-ketoglutarate (AKG) from wild-type and mutant IDH1/IDH2 enzymes through steered molecular dynamics (SMD) simulations, examining how mutations influence binding, stability and enzymatic behaviour.

Background: Isocitrate dehydrogenase (IDH) enzymes are essential for cellular metabolism, catalyzing the conversion of isocitrate to AKG in the tricarboxylic acid cycle. Mutations in IDH1 and IDH2 lead to the aberrant accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), disrupting normal metabolic processes and contributing to tumorigenesis.

Methods: SMD simulations were employed to investigate AKG unbinding from both wild-type and mutant IDH1/IDH2. External forces were applied to quantify rupture forces and assess differences in stability among enzyme variants.

Results: Wild-type IDH1 exhibited strong and stable AKG interactions, reflected by higher rupture forces and a greater number of hydrogen bonds, consistent with its normal catalytic function. In contrast, the R132H mutation in IDH1 weakened AKG binding, facilitating dissociation and potentially promoting 2-HG formation. Among IDH2 variants, the R140Q mutant demonstrated lower binding stability compared to R172K, while the wild-type enzyme maintained stronger interactions.

Conclusion: Mutations in IDH1 and IDH2 disrupt AKG binding and alter the stability, which may contribute to the pathological accumulation of 2-HG. These findings provide molecular insights into the oncogenic effects of IDH mutations and may aid in the development of targeted therapeutic strategies to inhibit mutant enzyme activity in cancer.

IDH突变对配体解结合的影响:来自定向分子动力学的见解。
目的:本研究通过操纵分子动力学(SMD)模拟研究α -酮戊二酸(AKG)与野生型和突变型IDH1/IDH2酶的解结合动力学,研究突变如何影响结合、稳定性和酶行为。背景:异柠檬酸脱氢酶(IDH)是细胞代谢必不可少的酶,在三羧酸循环中催化异柠檬酸转化为AKG。IDH1和IDH2的突变导致肿瘤代谢物2-羟戊二酸(2-HG)的异常积累,破坏正常的代谢过程并促进肿瘤的发生。方法:采用SMD模拟方法研究野生型和突变型IDH1/IDH2的AKG分离。应用外力来量化破裂力并评估酶变体之间稳定性的差异。结果:野生型IDH1表现出强烈而稳定的AKG相互作用,表现为更高的破裂力和更多的氢键,与正常的催化功能一致。相反,IDH1中的R132H突变削弱了AKG的结合,促进了解离,并可能促进2-HG的形成。在IDH2变异体中,与R172K相比,R140Q突变体的结合稳定性较低,而野生型酶保持了更强的相互作用。结论:IDH1和IDH2突变破坏AKG结合,改变稳定性,可能参与2-HG的病理性积累。这些发现为IDH突变的致癌作用提供了分子见解,并可能有助于开发靶向治疗策略,以抑制癌症中突变酶的活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.40
自引率
2.90%
发文量
186
审稿时长
3-8 weeks
期刊介绍: Current Topics in Medicinal Chemistry is a forum for the review of areas of keen and topical interest to medicinal chemists and others in the allied disciplines. Each issue is solely devoted to a specific topic, containing six to nine reviews, which provide the reader a comprehensive survey of that area. A Guest Editor who is an expert in the topic under review, will assemble each issue. The scope of Current Topics in Medicinal Chemistry will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, and structure-activity relationships. Medicinal chemistry is a rapidly maturing discipline. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. Current Topics in Medicinal Chemistry aims to contribute to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. The journal is essential for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important advances.
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