2D, 3D-QSAR and molecular docking of 4(1H)-quinolones analogues with antimalarial activities

作者：Jimenez Villalobos Thulie Paulinne; Gaitan Ibarra Ricardo; Montalvo Acosta Joel Jose

来源：Journal of Molecular Graphics and Modelling, 2013, 46: 105-124.

DOI：10.1016/j.jmgm.2013.10.002

• 4(1H)-Quinolones
• QSAR
• Docking
• Malaria
• Cytochrome bc(1)

Cytochrome bc(1) 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 bc(1) 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 bc(1) 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 bc(1) 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.

• 出版日期2013-11