Intelligent design and construction of novel APN-based theranostic probe driven by advanced computational methods
Intelligent design and construction of novel APN-based theranostic probe driven by advanced computational methods
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DOI：
10.1016/j.cclet.2023.108948
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发表时间：
2023-08
影响因子：
9.1
通讯作者：
Yingli Zhu;Jie Qian;Kunqian Yu;Jing Hou;Yeshuo Ma;Fei Chen;Jie Dong;Wenbin Zeng
中科院分区：
文献类型：
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作者：
Yingli Zhu;Jie Qian;Kunqian Yu;Jing Hou;Yeshuo Ma;Fei Chen;Jie Dong;Wenbin Zeng
具有光学信号和药理活性的多功能分子在药物开发、疾病诊断和基础理论研究中起着重要作用。氨肽酶N（APN）作为一种具有抗肿瘤潜力的肿瘤生物标志物，目前尚缺乏一种高精度的针对APN的治疗诊断探针。该策略利用先进的机器学习和分子动力学模拟，巧妙地采用构象诱导荧光恢复策略，实现功能片段的多目标优化和整合。通过这一策略，一个独特的“关-开”的治疗诊断探针，ABTP-DPTB，巧妙地构建通过荧光恢复点亮APN，依赖于构象诱导效应和溶剂限制。与普通诊断探头不同，ABTP-DPTB采用无基质连接的智能化设计，可实现长期原位成像。将该探针应用于多种环境中APN的检测和抑制，其体外抑制效果优于金标准药物bestatin。
Multifunctional molecules with both optical signal and pharmacological activity play an important role in drug development, disease diagnosis, and basic theoretical research. Aminopeptidase N (APN), as a representative tumor biomarker with anti-tumor potential, still lacks a high-precision theranostic probe specifically targeting it. In this study, a novel quaternity design strategy for APN theranostic probe was developed. This proposed strategy utilizes advanced machine learning and molecular dynamics simulations, and cleverly employs the strategy of conformation-induced fluorescence recovery to achieve multi-objective optimization and integration of functional fragments. Through this strategy, a unique “Off–On” theranostic probe,ABTP-DPTB, was ingeniously constructed to light up APN through fluorescence restoration, relying on conformation-induced effects and solvent restriction. Differ from the common diagnostic probes, the intelligent design with non-substrated linkage makesABTP-DPTBfor long-termin-situimaging. The fabricated probe was used for detecting and inhibiting APN in various environments, with a betterin vitroinhibitory than golden-standard drug bestatin.