Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
Centre for Infection and Immunity Studies (CIIS), School of Medicine, Sun Yat-Sen University, Shenzhen 518107, China.
Molecules. 2024 May 15;29(10):2312. doi: 10.3390/molecules29102312.
The ongoing COVID-19 pandemic still threatens human health around the world. The methyltransferases (MTases) of SARS-CoV-2, specifically nsp14 and nsp16, play crucial roles in the methylation of the N7 and 2'-O positions of viral RNA, making them promising targets for the development of antiviral drugs. In this work, we performed structure-based virtual screening for nsp14 and nsp16 using the screening workflow (HTVS, SP, XP) of Schrödinger 2019 software, and we carried out biochemical assays and molecular dynamics simulation for the identification of potential MTase inhibitors. For nsp14, we screened 239,000 molecules, leading to the identification of three hits A1-A3 showing N7-MTase inhibition rates greater than 60% under a concentration of 50 µM. For the SAM binding and nsp10-16 interface sites of nsp16, the screening of 210,000 and 237,000 molecules, respectively, from ZINC15 led to the discovery of three hit compounds B1-B3 exhibiting more than 45% of 2'-O-MTase inhibition under 50 µM. These six compounds with moderate MTase inhibitory activities could be used as novel candidates for the further development of anti-SARS-CoV-2 drugs.
持续的 COVID-19 大流行仍然威胁着全球人类的健康。SARS-CoV-2 的甲基转移酶（MTases），特别是 nsp14 和 nsp16，在病毒 RNA 的 N7 和 2'-O 位置的甲基化中发挥着关键作用，使它们成为开发抗病毒药物的有前途的靶点。在这项工作中，我们使用 Schrödinger 2019 软件的筛选工作流程（HTVS、SP、XP）对 nsp14 和 nsp16 进行了基于结构的虚拟筛选，并进行了生化测定和分子动力学模拟，以鉴定潜在的 MTase 抑制剂。对于 nsp14，我们筛选了 239000 个分子，确定了三个命中物 A1-A3，在 50μM 浓度下显示出 N7-MTase 抑制率大于 60%。对于 nsp16 的 SAM 结合和 nsp10-16 界面部位，分别从 ZINC15 中筛选出 210000 和 237000 个分子，发现了三个命中物 B1-B3，在 50μM 下对 2'-O-MTase 的抑制率超过 45%。这六种具有中等 MTase 抑制活性的化合物可以作为进一步开发抗 SARS-CoV-2 药物的新型候选药物。
