title: 2D, 3D-QSAR and molecular docking of 4(1H)-quinolones analogues with antimalarial activities.
abstract: Cytochrome bc1 has become a major focus as a molecular target in malaria parasites, which are the most important vector-borne infectious disease in the world. The inhibition of cytochrome bc1 blocks the mitochondrial respiratory chain and the consequent arrest of pyrimidine biosynthesis, which is essential for parasite development. The authors developed a theoretical study of two-dimensional, three-dimensional quantitative structure-activity relationships and a docking analysis of a series of 4(1H)-quinolones acting as cytochrome bc1 inhibitors. The predictive ability of the quantitative structure-activity relationship models was assessed using internal (leave-one-out cross-validation) and external (test set with 8 compounds) validation. From the two-dimensional quantitative structure-activity relationship models, the authors emphasized the following descriptors: GCUT_SLOGP_0, SLogP_VSA_5, Kier molecular flexibility index, electrophilicity index, the partition coefficient and the charge of atom 5 of the quinolone ring as the most important to explain the antimalarial activity of the compounds studied. Three-dimensional quantitative structure-activity relationship models showed that the substituents R1 and R4 in 4(1H)-quinolones analogues are key modulators to enhance the antimalarial activity. The appropriate binding conformations and orientations of these compounds interacting with cytochrome bc1 were also revealed by molecular docking. Based on the established models, 8 new compounds with highly predicted antimalarial activity have been theoretically designed and presented as a reference for synthesis and antimalarial evaluation.
authors.affiliation: Natural Products Group, Faculty of Pharmaceutical Science, Campus of Zaragocilla, University of Cartagena, Cartagena, Colombia.
authors.forename: Thulie Paulinne
authors.initials: TP
authors.lastname: Jiménez Villalobos
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gaitán Ibarra
authors.forename: Joel José
authors.initials: JJ
authors.lastname: Montalvo Acosta
mesh_terms: D020816:Amino Acid Motifs; D000962:Antimalarials / Q000737:chemistry*; D001665:Binding Sites; D015195:Drug Design; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D011804:Quinolines; D014450:Electron Transport Complex III
keywords: 4(1H)-Quinolones; Cytochrome bc(1); Docking; Malaria; QSAR