Laboratorio de Transducción de Señales y Movimiento Celular, Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Cuyo, Mendoza, Argentina.
Laboratorio de Biología Tumoral, Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de Cuyo, Mendoza, Argentina.
Comput Biol Med. 2024 Oct;181:108988. doi: 10.1016/j.compbiomed.2024.108988. Epub 2024 Aug 20.
Rosacea is a chronic dermatological condition that currently lacks a clear treatment approach due to an uncomprehensive knowledge of its pathogenesis. The main obstacle lies in understanding its etiology and the mode of action of the different drugs used. This study aims to clarify these aspects by employing drug repositioning. Using an in silico approach, we performed a transcriptomic analysis comparing samples from individuals with diverse types of rosacea to those from healthy controls to identify genes deregulated in this disease. Subsequently, we realized molecular docking and molecular dynamics studies to assess the binding affinity of drugs currently used to treat rosacea and drugs that target proteins interacting with, and thus affecting, proteins deregulated in rosacea. Our findings revealed that the downregulation of SKAP2 and upregulation of S100A7A in rosacea, could be involved in the pathogenesis of the disease. Furthermore, considering the drugs currently used for rosacea management, we demonstrated stable interactions between isotretinoin and BFH772 with SKAP2, and permethrin and PAC-14028 with S100A7A. Similarly, considering drugs targeting SKAP2 and S100A7A interactome proteins, we found that pitavastatin and dasatinib exert stable interactions with SKAP2, and lovastatin and tirbanibulin with S100A7A. In addition, we determine that the types of bonds involved in the interactions were different in SKAP2 from S100A7A. The drug-SKAP2 interactions are hydrogen bonds, whereas the drug-S100A7A interactions are of the hydrophobic type. In conclusion, our study provides evidence for the possible contribution of SKAP2 and S100A7A to rosacea pathology. Furthermore, it provides significant information on the molecular interactions between drugs and these proteins, highlighting the importance of considering structural features and binding interactions in the design of targeted therapies for skin disorders such as rosacea.
酒渣鼻是一种慢性皮肤病，由于对其发病机制的认识不全面，目前缺乏明确的治疗方法。主要障碍在于了解其病因和不同药物的作用方式。本研究旨在通过药物重定位来阐明这些方面。我们采用计算方法，对来自不同类型酒渣鼻患者和健康对照者的样本进行转录组分析，以确定该疾病中失调的基因。随后，我们进行了分子对接和分子动力学研究，以评估目前用于治疗酒渣鼻的药物和靶向与酒渣鼻中失调蛋白相互作用并因此影响这些蛋白的药物的结合亲和力。我们的研究结果表明，酒渣鼻中 SKAP2 的下调和 S100A7A 的上调可能与疾病的发病机制有关。此外，考虑到目前用于酒渣鼻管理的药物，我们证明了异维 A 酸和 BFH772 与 SKAP2 之间以及扑灭司林和 PAC-14028 与 S100A7A 之间存在稳定的相互作用。同样，考虑到靶向 SKAP2 和 S100A7A 相互作用体的药物，我们发现匹伐他汀和达沙替尼与 SKAP2 之间存在稳定的相互作用，而洛伐他汀和替吡努滨与 S100A7A 之间存在稳定的相互作用。此外，我们确定了相互作用中涉及的键的类型在 SKAP2 与 S100A7A 之间是不同的。药物-SKAP2 相互作用是氢键，而药物-S100A7A 相互作用是疏水型的。总之，我们的研究为 SKAP2 和 S100A7A 可能参与酒渣鼻病理学提供了证据。此外，它提供了关于药物与这些蛋白质之间分子相互作用的重要信息，突出了在设计针对皮肤疾病（如酒渣鼻）的靶向治疗时考虑结构特征和结合相互作用的重要性。
