Dynamic tail amine interactions drive isoform selectivity for potent human neuronal nitric oxide synthase inhibitors

IF 3.1 4区医学 Q3 CHEMISTRY, MEDICINAL

Medicinal Chemistry Research Pub Date : 2026-04-10 DOI:10.1007/s00044-026-03552-3

Amardeep Awasthi, Koon Mook Kang, Richard B. Silverman

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Abstract

Achieving isoform-selective inhibition of neuronal nitric oxide synthase (nNOS) remains a significant challenge due to the high structural similarity with other NOS isoforms. Here, we report the design, synthesis, and characterization of novel nNOS inhibitors 3 and 4, incorporating dimethylamino-substituted tail groups to exploit hnNOS-specific peripheral pocket interactions. Both compounds retained sub-20 nM potency against human nNOS with enhanced selectivity over endothelial (hn/he > 1500-fold) and inducible (hn/hi > 229-fold) isoforms. Molecular dynamics simulations and MM-GBSA calculations suggested that hnNOS selectivity arises from a dynamically formed cation-π interaction between the terminal amino group and W311(B), which is precluded in heNOS due to the steric hindrance from F105. PAMPA-BBB assays inḍdicated moderate blood-brain barrier permeability, supporting CNS applications. These findings highlight peripheral pocket interactions as key drivers of isoform selectivity and guide future nNOS inhibitor optimization for neurodegenerative diseases and melanoma.

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动态尾胺相互作用驱动有效的人类神经元一氧化氮合酶抑制剂的异构体选择性

由于神经元一氧化氮合成酶（nNOS）与其他一氧化氮合成酶（NOS）异构体具有高度的结构相似性，实现对其异构体的选择性抑制仍然是一个重大挑战。在这里，我们报道了新型nNOS抑制剂3和4的设计、合成和表征，结合二甲氨基取代的尾部基团来利用hnnos特异性外周口袋相互作用。这两种化合物对人nNOS的效力均保持在20 nM以下，对内皮（hn/he >； 1500倍）和诱导（hn/hi >； 229倍）亚型具有更高的选择性。分子动力学模拟和MM-GBSA计算表明，hnNOS的选择性来自末端氨基与W311(B)之间动态形成的阳离子-π相互作用，而在heNOS中由于F105的位阻而被排除。PAMPA-BBB检测inḍdicated中度血脑屏障通透性，支持中枢神经系统应用。这些发现强调了外周口袋相互作用是亚型选择性的关键驱动因素，并指导了未来神经退行性疾病和黑色素瘤的nNOS抑制剂优化。此图像的替代文本可能是使用AI生成的。

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来源期刊

Medicinal Chemistry Research 医学-医药化学

CiteScore

4.70

自引率

3.80%

发文量

162

审稿时长

5.0 months

期刊介绍： Medicinal Chemistry Research (MCRE) publishes papers on a wide range of topics, favoring research with significant, new, and up-to-date information. Although the journal has a demanding peer review process, MCRE still boasts rapid publication, due in part, to the length of the submissions. The journal publishes significant research on various topics, many of which emphasize the structure-activity relationships of molecular biology.