Suleman Muhammad, Moltrasio Chiara, Tricarico Paola Maura, Marzano Angelo Valerio, Crovella Sergio
Laboratory of Animal Research Center (LARC), Qatar University, Doha 2713, Qatar.
Dermatology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
Biomolecules. 2024 Nov 27;14(12):1521. doi: 10.3390/biom14121521.
Atopic dermatitis (AD) is a chronic inflammatory skin disease with rising prevalence, marked by eczematous lesions, itching, and a weakened skin barrier often tied to filaggrin gene mutations. This breakdown allows allergen and microbe entry, with thymic stromal lymphopoietin (TSLP) playing a crucial role by activating immune pathways that amplify the allergic response. TSLP's central role in AD pathogenesis makes it a promising therapeutic target. Consequently, in this study, we used the virtual drug screening, molecular dynamics simulation, and binding free energies calculation approaches to explore the African Natural Product Database against the TSLP protein. The molecular screening identified four compounds with high docking scores, namely SA_0090 (-7.37), EA_0131 (-7.10), NA_0018 (-7.03), and WA_0006 (-6.99 kcal/mol). Furthermore, the KD analysis showed a strong binding affinity of these compounds with TSLP, with values of -5.36, -5.36, -5.34, and -5.32 kcal/mol, respectively. Moreover, the strong binding affinity of these compounds was further validated by molecular dynamic simulation analysis, which revealed that the WA_0006-TSLP is the most stable complex with the lowest average RMSD. However, the total binding free energies were -40.5602, -41.0967, -27.3293, and -51.3496 kcal/mol, respectively, showing the strong interaction between the selected compounds and TSLP. Likewise, these compounds showed excellent pharmacokinetics characteristics. In conclusion, this integrative approach provides a foundation for the development of safe and effective treatments for AD, potentially offering relief to millions of patients worldwide.
特应性皮炎（AD）是一种患病率不断上升的慢性炎症性皮肤病，其特征为湿疹样皮损、瘙痒以及常与丝聚蛋白基因突变相关的皮肤屏障功能减弱。这种破坏使得变应原和微生物得以进入，胸腺基质淋巴细胞生成素（TSLP）通过激活放大过敏反应的免疫途径发挥关键作用。TSLP在AD发病机制中的核心作用使其成为一个有前景的治疗靶点。因此，在本研究中，我们使用虚拟药物筛选、分子动力学模拟和结合自由能计算方法，针对TSLP蛋白探索非洲天然产物数据库。分子筛选确定了四种对接分数较高的化合物，即SA_0090（-7.37）、EA_0131（-7.10）、NA_0018（-7.03）和WA_0006（-6.99千卡/摩尔）。此外，KD分析显示这些化合物与TSLP具有很强的结合亲和力，其值分别为-5.36、-5.36、-5.34和-5.32千卡/摩尔。此外，分子动力学模拟分析进一步验证了这些化合物的强结合亲和力，结果表明WA_0006-TSLP是最稳定的复合物，平均RMSD最低。然而，总结合自由能分别为-40.5602、-41.0967、-27.3293和-51.3496千卡/摩尔，表明所选化合物与TSLP之间存在强相互作用。同样，这些化合物表现出优异的药代动力学特性。总之，这种综合方法为开发安全有效的AD治疗方法奠定了基础，有望为全球数百万患者带来缓解。
