title: Design of the influenza virus inhibitors targeting the PA endonuclease using 3D-QSAR modeling, side-chain hopping, and docking.
abstract: With the emergence of drug resistance and the structural determination of the PA N-terminal domain (PAN), influenza endonucleases have become an attractive target for antiviral therapies for influenza infection. Here, we combined 3D-QSAR with side-chain hopping and molecular docking to produce novel structures as endonuclease inhibitors. First, a new molecular library was generated with side-chain hopping on an existing template molecule, L-742001, using an in-house fragment library that targets bivalent-cation-binding proteins. Then, the best 3D-QSAR model (AAAHR.500), with q(2)=0.76 and r(2)=0.97 from phase modeling, was constructed from 23 endonuclease inhibitors and validated with 17 test compounds. The AAAHR.500 model was then used to select effective candidates from the new molecular library. Combining 3D-QSAR with docking using Glide and Autodock, 13 compounds were considered the most likely candidate inhibitors. Docking studies showed that the binding modes of these compounds were consistent with the crystal structures of known inhibitors. These compounds could serve as potential endonuclease inhibitors for further biological activity tests.
authors.affiliation: College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China; High-Throughput Molecular Drug Discovery Center, Tianjin Joint Academy of Biomedicine and Technology, Tianjin 300457, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Yan
authors.affiliation: College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China; High-Throughput Molecular Drug Discovery Center, Tianjin Joint Academy of Biomedicine and Technology, Tianjin 300457, China.
authors.forename: Lijie
authors.initials: L
authors.lastname: Zhang
authors.affiliation: College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China; High-Throughput Molecular Drug Discovery Center, Tianjin Joint Academy of Biomedicine and Technology, Tianjin 300457, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300071, China.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300071, China; High-Throughput Molecular Drug Discovery Center, Tianjin Joint Academy of Biomedicine and Technology, Tianjin 300457, China. Electronic address: jianpinglin@nankai.edu.cn.
authors.forename: Jianping
authors.initials: J
authors.lastname: Lin
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites / Q000502:physiology; D003461:Crystallography; D015195:Drug Design; D004720:Endonucleases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006885:Hydroxybutyrates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009975:Orthomyxoviridae / Q000187:drug effects / Q000201:enzymology*; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017433:Protein Structure, Secondary; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006885:Hydroxybutyrates; C585288:L-742,001; D010880:Piperidines; D004720:Endonucleases
keywords: 3D-QSAR; Docking; Influenza virus endonuclease; Side-chain hopping; Virtual screening