比较分子动力学揭示LRRK2抑制剂如何区分G2019S与野生型

IF 3.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Chuancheng Wei, Choon Han Heh, Lei Cheng Lit, Sek Peng Chin
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引用次数: 0

摘要

富亮氨酸重复激酶2 (LRRK2)已成为帕金森病的关键药物靶点,突变选择性抑制剂为精准医学提供了有希望的潜力。然而,G2019S与野生型激酶之间的结构相似性给开发选择性抑制剂带来了重大挑战。尽管最近的进展导致了选择性靶向G2019S或野生型激酶的抑制剂,但这些抑制剂的选择性机制仍不清楚。我们采用分子动力学模拟来研究和探索激酶与配体的相互作用,并确定选择性的潜在机制。结果表明,配体结合驱动构象变化是影响选择性的关键因素,而不是配体结合的强度。配体诱导的构象变化导致激酶失稳和失活。此外,发现关键残基,如Tyr2018和Asp2017,在选择性中起关键作用。这些发现强调了将构象动力学纳入未来LRRK2突变选择性抑制剂设计中的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Comparative Molecular Dynamics Reveals How LRRK2 Inhibitors Distinguish G2019S from Wild-Type

Leucine-rich repeat kinase 2 (LRRK2) has become a critical drug target in Parkinson’s disease, with mutation-selective inhibitors offering promising potential for precision medicine. However, the structural similarity between G2019S and wild-type kinases presents a significant challenge in developing selective inhibitors. Although recent advances have led to inhibitors that selectively target G2019S or wild-type kinases, the selectivity mechanism of these inhibitors remains unclear. We employed molecular dynamics simulations to investigate and explore kinase-ligand interactions and identify the underlying mechanisms of selectivity. The results suggest that ligand binding drives the conformational changes, which is a key contributing factor to selectivity, rather than the strength of the ligand binding. The ligand-induced conformational changes lead to kinase destabilisation and inactivation. Additionally, key residues, such as Tyr2018 and Asp2017, were found to play pivotal roles in the selectivity. These insights underscore the importance of incorporating conformational dynamics into the design of future LRRK2 mutant-selective inhibitors.

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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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