title: De novo design of novel DNA-gyrase inhibitors based on 2D molecular fingerprints.
abstract: As increasing drug-resistance poses an emerging threat to public health, the development of novel antibacterial agents is critical. We developed a workflow consisting of various methods for de novo design. In the workflow, 2D-QSAR model based on molecular fingerprints was constructed to extract the bioactive molecular fingerprints from a data set of DNA-gyrase inhibitors with new structure and mechanism. These fingerprints were converted into molecular fragments which were recombined to generate compound library. The new compound library was virtually screened by LigandFit and Gold docking, and the results were further investigated by pharmacophore validation and binding mode analysis. The workflow successfully achieved a potential DNA-gyrase inhibitor. It could be applied to design more novel potential DNA-gyrase inhibitors and provide theoretical basis for further optimization of the hit compounds.
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Zhengui
authors.initials: Z
authors.lastname: Huang
authors.forename: Kejiang
authors.initials: K
authors.lastname: Lin
authors.forename: Qidong
authors.initials: Q
authors.lastname: You
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D027081:DNA Gyrase / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D020836:Protein Structure, Quaternary; D021281:Quantitative Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase