Culhuac Erick Bahena, Bello Martiniano
Laboratorio de Diseño y Desarrollo de Nuevos Fármacos e Innovación Biotecnológica, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico.
Facultad de Ciencias, Universidad Autónoma del Estado de México, Toluca 50000, Mexico.
Molecules. 2024 Apr 12;29(8):1765. doi: 10.3390/molecules29081765.
Allergic rhinitis (AR) is a prevalent inflammatory condition affecting millions globally, with current treatments often associated with significant side effects. To seek safer and more effective alternatives, natural sources like (UD) are being explored. However, UD's mechanism of action remains unknown. Therefore, to elucidate it, we conducted an in silico evaluation of UD phytochemicals' effects on known therapeutic targets of allergic rhinitis: histamine receptor 1 (HR1), neurokinin 1 receptor (NK1R), cysteinyl leukotriene receptor 1 (CLR1), chemoattractant receptor-homologous molecule expressed on type 2 helper T cells (CRTH2), and bradykinin receptor type 2 (BK2R). The docking analysis identified amentoflavone, alpha-tocotrienol, neoxanthin, and isorhamnetin 3-O-rutinoside as possessing a high affinity for all the receptors. Subsequently, molecular dynamics (MD) simulations were used to analyze the key interactions; the free energy of binding was calculated through Generalized Born and Surface Area Solvation (MMGBSA), and the conformational changes were evaluated. Alpha-tocotrienol exhibited a high affinity while also inducing positive conformational changes across all targets. Amentoflavone primarily affected CRTH2, neoxanthin targeted NK1R, CRTH2, and BK2R, and isorhamnetin-3-O-rutinoside acted on NK1R. These findings suggest UD's potential to treat AR symptoms by inhibiting these targets. Notably, alpha-tocotrienol emerges as a promising multi-target inhibitor. Further in vivo and in vitro studies are needed for validation.
变应性鼻炎（AR）是一种普遍存在的炎症性疾病，全球数百万人受其影响，目前的治疗方法常常伴有明显的副作用。为了寻找更安全、更有效的替代方法，人们正在探索像（UD）这样的天然来源。然而，UD的作用机制仍然未知。因此，为了阐明这一机制，我们对UD植物化学物质对变应性鼻炎已知治疗靶点的作用进行了计算机模拟评估：组胺受体1（HR1）、神经激肽1受体（NK1R）、半胱氨酰白三烯受体1（CLR1）、2型辅助性T细胞上表达的趋化因子受体同源分子（CRTH2）和缓激肽2型受体（BK2R）。对接分析确定穗花杉双黄酮、α-生育三烯酚、新黄质和异鼠李素3-O-芸香糖苷对所有这些受体具有高亲和力。随后，使用分子动力学（MD）模拟来分析关键相互作用；通过广义玻恩和表面积溶剂化（MMGBSA）计算结合自由能，并评估构象变化。α-生育三烯酚表现出高亲和力，同时还能在所有靶点上诱导正向构象变化。穗花杉双黄酮主要影响CRTH2，新黄质靶向NK1R、CRTH2和BK2R，而异鼠李素-3-O-芸香糖苷作用于NK1R。这些发现表明UD具有通过抑制这些靶点来治疗AR症状的潜力。值得注意的是，α-生育三烯酚是一种有前景的多靶点抑制剂。需要进一步的体内和体外研究来进行验证。
