Freedman Holly, Kundu Juthika, Tchesnokov Egor Petrovitch, Law John Lok Man, Nieman James A, Schinazi Raymond F, Tyrrell D Lorne, Gotte Matthias, Houghton Michael
Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
J Chem Inf Model. 2020 Dec 28;60(12):6566-6578. doi: 10.1021/acs.jcim.0c00742. Epub 2020 Dec 1.
The RNA-dependent RNA polymerase (RdRp) of norovirus is an attractive target of antiviral agents aimed at providing protection against norovirus-associated gastroenteritis. Here, we perform molecular dynamics simulations of the crystal structure of norovirus RdRp in complex with several known binders, as well as free-energy simulations by free-energy perturbation (FEP) to determine binding free energies of these molecules relative to the natural nucleotide substrates. We determine experimental EC values and nucleotide incorporation efficiencies for several of these compounds. Moreover, we investigate the mechanism of inhibition of some of these ligands. Using FEP, we screened a virtual nucleotide library with 121 elements for binding to the polymerase and successfully identified two novel chain terminators.
诺如病毒的RNA依赖性RNA聚合酶（RdRp）是抗病毒药物的一个有吸引力的靶点，旨在预防与诺如病毒相关的肠胃炎。在此，我们对诺如病毒RdRp与几种已知结合剂复合物的晶体结构进行了分子动力学模拟，并通过自由能微扰（FEP）进行了自由能模拟，以确定这些分子相对于天然核苷酸底物的结合自由能。我们测定了其中几种化合物的实验EC值和核苷酸掺入效率。此外，我们研究了其中一些配体的抑制机制。利用FEP，我们筛选了一个包含121种元素的虚拟核苷酸文库与聚合酶的结合情况，并成功鉴定出两种新型链终止剂。
