变异链球菌SrtA小分子抑制剂的虚拟筛选与验证  

Virtual screening and validation of small molecule inhibitors of Streptococcus mutans SrtA

作　　者：刘慕瑶 夏昕[1] 庄沛林[1] LIU Muyao;XIA Xin;ZHUANG Peilin(Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510120,China)

机构地区：[1]中山大学孙逸仙纪念医院,广州510120

出　　处：《实用口腔医学杂志》2025年第2期214-221,共8页Journal of Practical Stomatology

基　　金：广东省自然科学基金(编号:2018A0303130106)。

摘　　要：目的:寻找变异链球菌转肽酶A(SrtA)的靶向小分子抑制剂,为探寻新型有效的防龋药物提供实验依据。方法:采用虚拟筛选技术,以变异链球菌UA159的SrtA酶为受体,以氨基酸Cys205为共价结合位点,利用分子共价对接技术和ADMET成药性过滤从化合物天然小分子类药分子库中筛选出潜在小分子化合物,通过最低抑菌浓度实验与细菌黏附性实验筛选出抑黏附不抑菌的小分子化合物,并通过分子动力学模拟验证小分子化合物与SrtA的结合模式与稳定性。结果:经分子共价对接技术和ADMET成药性过滤筛选得到20种小分子化合物,其中AK-968/40369373、AK-968/40385877等小分子化合物对变异链球菌黏附的抑制作用优于反式查尔酮,差异有统计学意义(P<0.05),分子动力学模拟验证证实AK-968/40369373,AK-968/40385877均可与SrtA形成稳定的共价结合。结论:虚拟筛选与验证是筛选变异链球菌SrtA潜在靶向抑制剂的有效方法,该实验筛选得到的AK-968/40369373、AK-968/40385877等小分子化合物有望作为新型变异链球菌SrtA的靶向小分子抑制剂。Objective:The objective of this study was to search for targeted small molecule inhibitors of Sortase A(SrtA)of Streptococcus mutans(S.mutans),and to provide an experimental basis for the exploration of novel and effective anti-caries drugs.Methods:Using the crystal structure of SrtA enzyme of S.mutans UA159(PDB code:4TQX)as the receptor and amino acid Cys205 as the covalent binding site,we screened potential small molecule compounds from the natural small molecule drug-like molecule libraries of the compounds using molecular covalent docking technology and ADMET drug-forming filtration.The study screened small molecule compounds that inhibit adhesion without antibacterial effect,as determined by the minimum inhibitory concentration(MIC)and bacterial adhesion experiments.The binding modes and stabilities of the small molecule compounds were verified through molecular dynamics simulation.Results:A total of 20 small molecule compounds were selected by molecular covalent docking technology and ADMET druggability filtration,among which AK-968/40369373 and AK-968/40385877 inhibited the adhesion of S.mutans better than trans-chalcone,and the difference was statistically significant(P<0.05).Molecular dynamics simulations confirmed that AK-968/40369373 and AK-968/40385877 could form stable covalent binding to SrtA.Conclusion:Virtual screening and validation are effective methods for selecting potential targeting inhibitors of SrtA.The small-molecule compounds AK-968/40369373 and AK-968/40385877 obtained in this study are expected to be used as small-molecule inhibitors targeting S.mutans SrtA.

关 键 词：变异链球菌 转肽酶A(SrtA) 虚拟筛选 小分子抑制剂 

分 类 号：R780.2[医药卫生—口腔医学]