2D and 3D-QSAR, molecular docking and ADMET properties in silico studies of azaaurones as antimalarial agents
Malaria persists as the most important infectious vector-borne disease in the world. Inhibition of the mitochondrial respiratory chain enzyme cytochrome bc1 has become the major focus as a molecular target in malaria parasites. Azaaurone derivatives have the potential to inhibit the mitochondrial respiratory chain of Plasmodium falciparum. Thus, in the aim of improving and proposing new molecules designed for antimalarial activity, we have carried out a theoretical study of two-dimensional, three-dimensional-quantitative structure-activity relationships (QSAR) and docking analysis of a series of 53 azaaurone acting as Qo site inhibitors in cytochrome b. The generated 2D-QSAR model showed good correlation coefficients of 0.871 and very good prediction coefficients of the test set, 0.914. The predictive ability of the 2DQSAR models was assessed using Y-randomization test, internal (leave-one-out cross-validation) and external (test set with 11 compounds) validation. The 3D-QSAR model was generated using Comparative Molecular Similarity Indices Analysis (CoMSIA). The best CoMSIA model with Q2 = 0.739, R2 = 0.844 and R_pred^2 = 0.932 was evaluated using Y-randomization test. The proposed models gave significant statistical quality. The results of molecular docking revealed that azaaurone specifically interacts with the residues his183 and his82, this result was validated with a new validation criterion. Moreover, this is the first theoretical study showing molecule acting on the active site of heme bL. A good consistency between theoretical, 2D, 3D-SQAR and molecular docking studies provided advice for the design of new drug candidates.