Molecular Dynamics-Ensemble Docking and Biophysical Studies for Structure-Based Identification of Non-Amino Acidic Ligands of DDAH-1,Journal of Chemical Information and Modeling

当前位置： X-MOL 学术 › J. Chem. Inf. Model. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Molecular Dynamics-Ensemble Docking and Biophysical Studies for Structure-Based Identification of Non-Amino Acidic Ligands of DDAH-1
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-08-23 , DOI: 10.1021/acs.jcim.4c01150
Carlo Bigiotti ₁ , Elisa Bianconi ₁ , Luana Ruta ₂ , Silvia Grottelli ₂ , Alice Coletti ₁ , Mirco Dindo ₂ , Andrea Carotti ₁ , Barbara Cellini ₂ , Antonio Macchiarulo ₁

Affiliation

Dimethylarginine dimethylaminohydrolase-1 (DDAH-1) accounts for the catabolism of the endogenous inhibitors of nitric oxide (NO) synthases, namely, ADMA (N^ω,N^ω-dimethyl-l-arginine) and NMMA (N^ω-monomethyl-l-arginine). Inhibition of DDAH-1 may prove a therapeutic benefit in diseases associated with elevated nitric oxide (NO) levels by providing a tissue-specific increase of ADMA and NMMA. In this work, we have used molecular dynamics to generate a pool of DDAH-1 conformations in the apo and holo forms. Ensemble docking has been instrumental in screening an in-house fragment-based library of 824 compounds. Resulting virtual hits have been validated for their binding activity to recombinant human DDAH-1 using microscale thermophoresis (MST). As a key result, three non-amino acidic ligands of DDAH-1 (VIS212, VIS268, VIS726) are identified with higher binding efficiency index than ADMA. Amid these compounds, purpurogallin (VIS726) proves a potent ligand of DDAH-1, showing a mixed behavior of enzymatic inhibition in a biochemical assay. This finding widens the panel of known molecular targets of purpurogallin and provides clues into the molecular mechanisms of its cellular NO inhibition activity as well as its anti-inflammatory and neuroprotective effects.

中文翻译：

基于结构鉴定 DDAH-1 非氨基酸配体的分子动力学-系综对接和生物物理研究

二甲基精氨酸二甲氨基水解酶-1 (DDAH-1) 负责一氧化氮 (NO) 合酶内源性抑制剂的分解代谢，即 ADMA ( N ^ω , N ^{ω -}二甲基- l -精氨酸) 和 NMMA ( N ^ω -单甲基- l - 精氨酸) -精氨酸）。通过提供组织特异性的 ADMA 和 NMMA 抑制，DDAH-1 的抑制可能对与一氧化氮 (NO) 水平升高相关的疾病具有治疗益处。在这项工作中，我们利用分子动力学生成了 apo 和 Holo 形式的 DDAH-1 构象池。集成对接在筛选包含 824 种化合物的内部片段库方面发挥了重要作用。使用微尺度热泳动 (MST) 验证了所得虚拟命中与重组人 DDAH-1 的结合活性。作为一个关键结果，DDAH-1 的三个非氨基酸配体（VIS212、VIS268、VIS726）被鉴定为具有比 ADMA 更高的结合效率指数。在这些化合物中，红没食子素 (VIS726) 被证明是 DDAH-1 的有效配体，在生化测定中显示出酶抑制的混合行为。这一发现扩大了红没食子素的已知分子靶点范围，并为其细胞 NO 抑制活性及其抗炎和神经保护作用的分子机制提供了线索。

更新日期：2024-08-23

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南