title: Residue-based design of small molecule inhibitor for H1N1, H5N1 and H7N1 mutants.
abstract: Point mutations H274Y and N294S can lead to resistance of influenza virus strains to some drug molecules. Recently, a large number of experiments has focused on the many frameworks and catalytic residues thought to prevent the efficacy of anti-flu drugs. In the past, most research has considered the role of drugs in rigid proteins rather than in flexible proteins. In this study, we used molecular dynamics simulation (MD) combined with structure- and ligand-based drug design (SBDD and LBDD) methods to study dynamic interaction and protein dynamics correlation statistics between compounds and both the framework and catalytic residues in influenza virus N1 strains. Drug candidates were screened using the IC50 of the docking result predicted by support vector machine, multiple linear regression, and genetic function approximation (P < 0.001). As shown by MD, saussureamine C and diiodotyrosine have a protein dynamics correlation similar to that of sialic acid, and both can participate in hydrogen bond formation with loop, framework, and catalytic residues. Our in silico findings suggest that saussureamine C can inhibit H274Y and N294S mutants, and that diiodotyrosine can also inhibit N294S mutants. Therefore, the drugs saussureamine C and diiodotyrosine have the potential to produce inhibitory effects on wild-type influenza virus and some N1 mutants.
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, 40402, Taiwan.
authors.forename: Weng Ieong
authors.initials: WI
authors.lastname: Tou
authors.affiliation: Department of Bioinformatics and Medical Engineering, Asia University, Taichung, 41354, Taiwan.
authors.forename: Kun-Lung
authors.initials: KL
authors.lastname: Chang
authors.affiliation: School of Post-Baccalaureate Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan.|Department of Chinese Pediatrics, China Medical University Hospital, Taichung, 40402, Taiwan.
authors.forename: Tung-Ti
authors.initials: TT
authors.lastname: Chang
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, 40402, Taiwan.|Department of Neurology, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Cheng-Chun
authors.initials: CC
authors.lastname: Lee
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, 40402, Taiwan. ycc929@MIT.EDU.|Department of Bioinformatics and Medical Engineering, Asia University, Taichung, 41354, Taiwan. ycc929@MIT.EDU.|Research Center for Chinese Medicine and Acupuncture, China Medical University, Taichung, 40402, Taiwan. ycc929@MIT.EDU.|Department of Medical Research, China Medical University Hospital, Taichung, 40404, Taiwan. ycc929@MIT.EDU.
authors.forename: Calvin Yu-Chian
authors.initials: CY
authors.lastname: Chen
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry*; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry* / Q000235:genetics; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry* / Q000235:genetics; D057916:Influenza A Virus, H7N1 Subtype / Q000737:chemistry* / Q000235:genetics; D062105:Molecular Docking Simulation; D012794:Sialic Acids / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D012794:Sialic Acids
keywords: Drug discovery; H1N1; H5N1; H7N1; Traditional Chinese medicine