title: Combined QSAR-based virtual screening and fluorescence binding assay to identify natural product mediators of Interferon Regulatory Factor 7 (IRF-7) in pulmonary infection.
abstract: Interferon regulatory factor-7 (IRF-7) is involved in pulmonary infection and pneumonia. Here, a synthetic strategy that combined quantitative structure-activity relationship (QSAR)-based virtual screening and in vitro binding assay was described to identify new and potent mediator ligands of IRF-7 from natural products. In the procedure, a QSAR scoring function was developed and validated using Gaussian process (GP) regression and a structure-based set of protein-ligand affinity data. By integrating hotspot pocket prediction, pharmacokinetics profile analysis and molecular docking calculations, the scoring function was successfully applied to virtual screening against a large library of structurally diverse, drug-like natural products. With the method we were able to identify a number of potential hits, from which several compounds were found to have moderate or high affinity to IRF-7 using fluorescence binding assays, with dissociation constants Kdat micromolar level. We have also examined the structural basis and noncovalent interactions of computationally modelled IRF-7 complex with its potent ligands. It is revealed that hydrophobic forces and van der Waals contacts play a central role in stabilization of the complex architecture, while few hydrogen bonds confer additional specificity for the protein-ligand recognition.
authors.affiliation: a Centre of Infectious Diseases , West China Hospital, Sichuan University , Chengdu , China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: a Centre of Infectious Diseases , West China Hospital, Sichuan University , Chengdu , China.
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.affiliation: a Centre of Infectious Diseases , West China Hospital, Sichuan University , Chengdu , China.
authors.forename: H
authors.initials: H
authors.lastname: Ye
authors.affiliation: a Centre of Infectious Diseases , West China Hospital, Sichuan University , Chengdu , China.
authors.forename: X
authors.initials: X
authors.lastname: Lv
mesh_terms: D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology; D005453:Fluorescence; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism*; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D001688:Biological Products; D050839:Interferon Regulatory Factor-7; D008024:Ligands
keywords: Interferon regulatory factor-7; natural product; pneumonia; pulmonary infection; quantitative structure–activity relationship