title: Combinatorially-generated library of 6-fluoroquinolone analogs as potential novel antitubercular agents: a chemometric and molecular modeling assessment.
abstract: The virtual combinatorial chemistry approach as a methodology for generating chemical libraries of structurally-similar analogs in a virtual environment was employed for building a general mixed virtual combinatorial library with a total of 53.871 6-FQ structural analogs, introducing the real synthetic pathways of three well known 6-FQ inhibitors. The druggability properties of the generated combinatorial 6-FQs were assessed using an in-house developed drug-likeness filter integrating the Lipinski/Veber rule-sets. The compounds recognized as drug-like were used as an external set for prediction of the biological activity values using a neural-networks (NN) model based on an experimentally-determined set of active 6-FQs. Furthermore, a subset of compounds was extracted from the pool of drug-like 6-FQs, with predicted biological activity, and subsequently used in virtual screening (VS) campaign combining pharmacophore modeling and molecular docking studies. This complex scheme, a powerful combination of chemometric and molecular modeling approaches provided novel QSAR guidelines that could aid in the further lead development of 6-FQs agents.
authors.affiliation: National Institute of Chemistry, Ljubljana, Slovenia.
authors.forename: Nikola
authors.initials: N
authors.lastname: Minovski
authors.forename: Andrej
authors.initials: A
authors.lastname: Perdih
authors.forename: Tom
authors.initials: T
authors.lastname: Solmajer
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D024841:Fluoroquinolones / Q000737:chemistry*; D046609:Libraries, Digital; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D016571:Neural Networks, Computer; D021281:Quantitative Structure-Activity Relationship; D054852:Small Molecule Libraries; D012984:Software
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D054852:Small Molecule Libraries