The Development and Design Strategy of Leucine-Rich Repeat Kinase 2 Inhibitors: Promising Therapeutic Agents for Parkinson’s Disease,Journal of Medicinal Chemistry

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The Development and Design Strategy of Leucine-Rich Repeat Kinase 2 Inhibitors: Promising Therapeutic Agents for Parkinson’s Disease
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-02-09 , DOI: 10.1021/acs.jmedchem.2c01552
Xu Tang ₁ , Shuaishuai Xing ₁ , Mingkang Ma ₁ , Ziwei Xu ₁ , Qianwen Guan ₁ , Yuting Chen ₁ , Feng Feng _{2,

3} , Wenyuan Liu ₁ , Tingkai Chen ₁ , Yao Chen ₄ , Haopeng Sun ₁

Affiliation

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting millions of people worldwide. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factor for PD. Elevated LRRK2 kinase activity is found in idiopathic and familial PD cases. LRRK2 mutations are involved in multiple PD pathogeneses, including dysregulation of mitochondrial homeostasis, ciliogenesis, etc. Here, we provide a comprehensive overview of the biological function, structure, and mutations of LRRK2. We also examine recent advances and challenges in developing LRRK2 inhibitors and address prospective protein-based targeting strategies. The binding mechanisms, structure–activity relationships, and pharmacokinetic features of inhibitors are emphasized to provide a comprehensive compendium on the rational design of LRRK2 inhibitors. We hope that this publication can serve as a guide for designing novel LRRK2 inhibitors based on the summarized facts and perspectives.

中文翻译：

富含亮氨酸重复激酶 2 抑制剂的开发和设计策略：帕金森氏病的有前途的治疗药物

帕金森病 (PD) 是一种进行性神经退行性疾病，影响着全世界数百万人。编码富含亮氨酸的重复激酶 2 (LRRK2) 的基因突变是 PD 最常见的遗传风险因素。在特发性和家族性 PD 病例中发现 LRRK2 激酶活性升高。LRRK2 突变涉及多种 PD 发病机制，包括线粒体稳态失调、纤毛发生等。在这里，我们全面概述了 LRRK2 的生物学功能、结构和突变。我们还研究了开发 LRRK2 抑制剂的最新进展和挑战，并解决了基于蛋白质的前瞻性靶向策略。结合机制、构效关系、强调了抑制剂的药代动力学特征，以提供有关 LRRK2 抑制剂合理设计的综合纲要。我们希望本出版物可以作为基于总结的事实和观点设计新型 LRRK2 抑制剂的指南。

更新日期：2023-02-09

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