Brecher Matthew, Chen Hui, Li Zhong, Banavali Nilesh K, Jones Susan A, Zhang Jing, Kramer Laura D, Li Hongmin
Wadsworth Center, New York State Department of Health , 120 New Scotland Avenue, Albany, New York 12208, United States.
Department of Biomedical Sciences, School of Public Health, State University of New York , P.O. Box 509, Albany, New York 12201 United States.
ACS Infect Dis. 2015 Aug 14;1(8):340-9. doi: 10.1021/acsinfecdis.5b00070. Epub 2015 Jul 31.
Flavivirus methyltransferase (MTase) is essential for viral replication. Here we report the identification of small molecules through virtual screening that putatively bind to the SAM-binding site of flavivirus MTase and inhibit its function. Six of these computationally predicted binders were identified to show significant MTase inhibition with low micromolar inhibitory activity. The most active compounds showed broad-spectrum activity against the MTase proteins of other flaviviruses. Two of these compounds also showed low cytotoxicity and high antiviral efficacy in cell-based assays. Competitive binding analyses indicated that the inhibitors performed their inhibitory function through competitive binding to the SAM cofactor binding site of the MTase. The crystal structure of the MTase-inhibitor complex further supports the mode of action and provides routes for their further optimization as flavivirus MTase inhibitors.
黄病毒甲基转移酶（MTase）对病毒复制至关重要。在此，我们报告通过虚拟筛选鉴定出可能与黄病毒MTase的SAM结合位点结合并抑制其功能的小分子。这些通过计算预测的结合剂中有六种被鉴定出具有显著的MTase抑制作用，抑制活性低至微摩尔级别。活性最高的化合物对其他黄病毒的MTase蛋白具有广谱活性。其中两种化合物在基于细胞的试验中也显示出低细胞毒性和高抗病毒效力。竞争性结合分析表明，抑制剂通过与MTase的SAM辅因子结合位点竞争性结合来发挥其抑制功能。MTase-抑制剂复合物的晶体结构进一步支持了其作用模式，并为将其进一步优化为黄病毒MTase抑制剂提供了途径。
