首页 | 本学科首页   官方微博 | 高级检索  
     检索      


Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors
Authors:Keli Zong  Lei Xu  Yuxin Hou  Qian Zhang  Jinjing Che  Lei Zhao  Xingzhou Li
Institution:1.Chemical Engineering and Environmental Engineering, College of Chemistry, Liaoning Shihua University, Fushun 113001, China;2.Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China;3.Tianjin Children Hospital, Tianjin Medical University, Tianjing 300074, China;4.Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
Abstract:Influenza A virus is the main cause of worldwide epidemics and annual influenza outbreaks in humans. In this study, a virtual screen was performed to identify compounds that interact with the PB2 cap-binding domain (CBD) of influenza A polymerase. A virtual screening workflow based on Glide docking was used to screen an internal database containing 8417 molecules, and then the output compounds were selected based on solubility, absorbance, and structural fingerprints. Of the 16 compounds selected for biological evaluation, six compounds were identified that rescued cells from H1N1 virus-mediated death at non-cytotoxic concentrations, with EC50 values ranging from 2.5–55.43 μM, and that could bind to the PB2 CBD of H1N1, with Kd values ranging from 0.081–1.53 μM. Molecular dynamics (MD) simulations of the docking complexes of our active compounds revealed that each compound had its own binding characteristics that differed from those of VX-787. Our active compounds have novel structures and unique binding modes with PB2 proteins, and are suitable to serve as lead compounds for the development of PB2 inhibitors. An analysis of the MD simulation also helped us to identify the dominant amino acid residues that play a key role in binding the ligand to PB2, suggesting that we should focus on increasing and enhancing the interaction between inhibitors and these major amino acids during lead compound optimization to obtain more active PB2 inhibitors.
Keywords:virtual screening  influenza virus  polymerase basic protein 2  inhibitor  molecular dynamics simulations
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号