3D-QSAR, docking and ADMET properties of aurone analogues as antimalarial agents

Heliyon. 2020 Apr 18;6(4):e03580. doi: 10.1016/j.heliyon.2020.e03580. eCollection 2020 Apr.


The development of multi-resistant strains of plasmodium parasite has become a global problem, therefore, the discovery of new antimalarial agents is the only available solution. In order to improve and propose new compounds with antimalarial activity, the three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking studies were carried on aurone analogues acting as Qo site inhibitors in cytochrome b. The 3D-QSAR model was established in this study based on the Comparative Molecular Field Analysis (CoMFA) and the Comparative Molecular Similarity Indices Analysis (CoMSIA). The good predictability was obtained using the CoMFA model (Q2 = 0.5; R2 = 0.97; R pred 2 = 0.72) and the best CoMSIA model (Q2 = 0.526; R2 = 0.915; R pred 2 = 0.765). The predictive capacity of the developed model was evaluated through external validation using a test set compound and an applicability domain technique. In this study, the Steric, electrostatic and hydrogen bond acceptor fields played a key role in antimalarial activity. The results of the molecular docking revealed theoretically the importance of the residues his183 and his82 in the active site of the heme bL, this result was validated by a new assessment method. Based on the previous results, we designed several new potent Cytochrome b inhibitors and their inhibitory activities were predicted by the best model. Furthermore, these new inhibitors were analyzed for their ADMET properties and drug likeness. These results would be of great help in leading optimization for new drug discovery that can solve the problem of multiple drug resistance.

Keywords: 3D-QSAR; ADMET properties; Aurone; Azaaurone; Druglikeness; Malarial; Molecular docking; Pharmaceutical chemistry; Theoretical chemistry.