基于促黑色素合成分子的结构相似性筛选潜在白癜风的治疗药物

Screening of potential therapeutic drugs for vitiligo based on the structural similarity of melanin-promoting molecules

目的白癜风是一种色素沉着减退性皮肤病,因发病机制复杂,治愈率低,需要寻找新的先导化合物,本文拟根据已报道的促黑色素生成化合物分子结构去筛选新的化合物分子。方法收集PubMed中已报道促黑色素生成的化合物分子,在in silico水平根据2D结构相似性聚类与Tanimoto相似性评分、2D QSAR和分子对接筛选能促进黑色素生成的化合物。在in vitro水平建立B16F10促黑色素生成细胞模型,通过对比促黑色素生成量效关系,酪氨酸酶活性,以及黑色素生成途径的基因表达情况综合评价潜在活性分子。结果共收集47个促黑色素生成的化合物并最终筛选出Ermanin,Tamarixetin,Quercetin 3,4’-dimethyl ether,这3个化合物均能引起B16F10细胞黑色素积累,对比黑色素含量及酪氨酸酶活性,3个化合物中Ermanin效果最好;qPCR结果显示Ermanin可以显著增强TYR和MITF基因的表达且与同浓度阳性药8-MOP组比具有显著性(P<0.05),Tamarixetin可以增强TYR,TRP-1,DCT,MITF基因的表达,Quercetin 3,4′-dimethyl ether高浓度组能增强TYR,DCT基因的表达。结论以Ermanin为代表的甲氧基黄酮化合物具有促黑色素生成而有望作为治疗白癜风的先导化合物。

Objective Vitiligo is a hypopigmented skin disease.It is necessary to find new lead compounds due to its complex pathogenesis and low cure rate.This article intends to screen new compound molecules based on the reported molecular structures of melanin-promoting compounds.Methods Collect the compounds that have been reported to promote melanin production in PubMed,and screen the compounds that can promote melanin production based on 2D structural similarity clustering and Tanimoto similarity score,2D QSAR and molecular docking at the in silico level.The B16F10 melanin-promoting cell model was established at the in vitro level,and the potential active molecules were comprehensively evaluated by comparing the melanin-promoting dose-effect relationship,tyrosinase activity,and gene expression of the melanin production pathway.Results A total of 47 potential melanin-promoting compounds were collected through literature mining and Ermanin,Tamarixetin,Quercetin 3,4′-dimethyl ether were finally screened.these 3 compounds can cause the accumulation of melanin in B16F10 cells.Comparing the melanin content and tyrosinase activity,Ermanin has the best effect among the 3 compounds,qPCR results showed that Ermanin can significantly enhance the expression of TYR and MITF genes and was significantly higher than that of the positive drug 8-MOP group at the same concentration(P<0.05),Tamarixetin can enhance the expression of TYR,TRP-1,DCT,MITF genes,and the high concentration group of Quercetin 3,4′-dimethyl ether can enhance the expression of TYR,DCT genes.Conclusion The methoxyflavonoids represented by Ermanin have melanin production and are expected to be leading compounds for the treatment of vitiligo.