Vibrational, theoretical characterisation and <i>In Silico</i> investigation of Norcinnamolaurine: a natural lead for inhibiting AURKA and overcoming immune evasion in Triple-Negative Breast Cancer

Alkaloids represent a diverse category of natural compounds with noteworthy pharmacological and therapeutic applications. Benzylisoquinoline alkaloids (BIAs) are distinguished by their varied structures and potential medicinal properties. This study specifically investigates Norcinnamolaurine, a BIA found in multiple species and acknowledged for its therapeutic advantages. In the current investigation, we comprehensively analyzed Norcinnamolaurine, encompassing Frontier Molecular Orbital studies, vibrational spectroscopy, nonlinear optical properties, natural bond orbital evaluations, and Fukui's analysis. Additionally, we executed an E-pharmacophore-based screening utilizing the AURKA-Norcinnamolaurine complex. The generated hypothesis underwent database screening; lead compounds from the Natural Product and Drug Bank databases exhibited enhanced binding affinities ranging from −8.602 to −7.148 kcal/mol, demonstrating improved interactions within the AURKA binding pocket. Subsequently, the identified lead compounds were subjected to further analysis via MMGBSA, DFT, and Molecular Dynamics Simulations (MDS). Our findings indicate that Norcinnamolaurine exhibits a superior binding affinity towards the target protein. Significant outcomes were also observed in the vibrational and FMO studies. Moreover, MDS analysis revealed that the resultant complexes maintained relative stability, exhibiting minimal deviation and fluctuations. This stability was corroborated through additional assessments using MMPBSA and PCA/FEL methodologies.生物碱是一类结构多样的天然化合物，在药理学与治疗学领域具有重要应用价值。苄基异喹啉类生物碱（Benzylisoquinoline Alkaloids, BIAs）以其多样的结构与潜在的药用特性而著称。本研究聚焦于去甲肉桂月桂碱（Norcinnamolaurine）——一种广泛分布于多个物种中且被证实具备治疗益处的BIA类生物碱，对其展开专项探究。在本研究中，我们对去甲肉桂月桂碱开展了全面分析，涵盖前线分子轨道（Frontier Molecular Orbital, FMO）研究、振动光谱分析、非线性光学特性探究、自然键轨道（Natural Bond Orbital, NBO）评估以及福井分析（Fukui's analysis）。此外，我们基于电子药效团（E-pharmacophore），以极光激酶A（Aurora Kinase A, AURKA）-去甲肉桂月桂碱复合物为模型开展了筛选实验。所构建的药效团假说经数据库筛选后，从天然产物数据库与Drug Bank数据库中获得的先导化合物，其结合亲和力介于-8.602至-7.148 kcal/mol之间，在AURKA结合口袋中展现出更优的相互作用效果。随后，我们采用分子力学-广义玻恩表面积法（MMGBSA）、密度泛函理论（Density Functional Theory, DFT）以及分子动力学模拟（Molecular Dynamics Simulations, MDS）对筛选得到的先导化合物进行了深入分析。研究结果表明，去甲肉桂月桂碱对靶蛋白展现出更优异的结合亲和力。振动光谱与前线分子轨道研究亦获得了具有重要意义的结果。此外，分子动力学模拟分析显示，所构建的复合物保持了相对稳定性，仅存在极小的偏差与波动；这一稳定性结论通过分子力学-泊松玻尔兹曼表面积法（MMPBSA）以及主成分分析（Principal Component Analysis, PCA）/自由能面（Free Energy Landscape, FEL）等额外评估手段得到了验证。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于天然生物碱Norcinnamolaurine，通过综合的计算化学和生物信息学方法（如振动光谱、分子对接和动力学模拟）研究其抑制AURKA蛋白和克服三阴性乳腺癌免疫逃逸的潜力。分析表明Norcinnamolaurine对靶蛋白具有高结合亲和力，且形成的复合物在模拟中结构稳定，为开发新型抗癌先导化合物提供了理论基础。