Shi Zhongling, Liu Na, Zhao Fabao, Kang Dongwei, De Jonghe Steven, Neyts Johan, Gao Ni, Liu Xinyong
Department of Medicinal Chemistry, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, Jinan 250012, China.
Molecular, Structural and Translational Virology Research Group, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Int J Mol Sci. 2025 Jun 12;26(12):5625. doi: 10.3390/ijms26125625.
Human noroviruses (HuNoVs) are the primary cause of acute viral gastroenteritis. There are no antivirals or vaccines available to treat and/or prevent HuNoV. Norovirus 3C-like protease (3CLpro) is essential for viral replication; consequently, the inhibition of this enzyme is a fruitful avenue for antinorovirus therapeutics. To discover novel 3CLpro inhibitors with diverse scaffolds, a multi-stage virtual screening approach was performed by docking >10 million compounds into the 3CLpro catalytic site. An initial subset of 18 compounds was selected, and compounds and were identified as the best two molecules. Molecular dynamics (MD) simulations and binding free energy calculations (MM/GBSA) of and were performed to elucidate the binding mechanisms. The ADMET properties were also estimated to predict the potential druggability of representative molecules. All 18 compounds were evaluated for their antinorovirus activity and cytotoxicity in a cell-based replicon system. This work could provide information for the development of 3CL pro inhibitors.
人诺如病毒（HuNoVs）是急性病毒性肠胃炎的主要病因。目前尚无用于治疗和/或预防HuNoV的抗病毒药物或疫苗。诺如病毒3C样蛋白酶（3CLpro）对病毒复制至关重要；因此，抑制这种酶是抗诺如病毒治疗的一个有效途径。为了发现具有不同骨架的新型3CLpro抑制剂，通过将超过1000万种化合物对接至3CLpro催化位点进行了多阶段虚拟筛选。选择了18种化合物的初始子集，并确定化合物 和 为最佳的两个分子。对化合物 和 进行了分子动力学（MD）模拟和结合自由能计算（MM/GBSA）以阐明结合机制。还估计了ADMET性质以预测代表性分子的潜在成药可能性。在基于细胞的复制子系统中评估了所有18种化合物的抗诺如病毒活性和细胞毒性。这项工作可为3CL pro抑制剂的开发提供信息。
