3D-QSAR and Molecular Mechanics Study for the Differences in the Azole Activity against Yeastlike and Filamentous Fungi and Their Relation to P450DM Inhibition. 1. 3-Substituted-4(3H)-quinazolinones

Abstract

A combination between 3D-QSAR and molecular mechanics (MM)-docking study was used as a tool to detail and model the mechanism of action of 46 antifungal azoles. Two methods of alignment of the ligands were performed: (i) alignment of the main skeleton without substituents and (ii) alignment of a defined substructure. The best model is characterized by q(2) with the values of 0.70 for yeastlike (yeast), 0.66 for filamentous fungi, and 0.70 for the selectivity against filamentous fungi. 3D-QSAR regression maps derived from six models were used to identify the regions responsible for the differences in the compounds activity against yeast and filamentous fungi. The binding energy of the important substructures (Local Binding Energy-LBE) and its standard deviation were calculated in order to demonstrate quantitatively the contribution of substituents reflecting the diversity of the antifungal activity. The comparisons of these results with the same regions of the contour maps indicated a good correspondence between the 3D-QSAR and MM (LBE) approaches allowing association between the maps and the participating residues in the active sites of P450DM of C. albicans and A. fumigatus. The pi-pi interactions of two or more aromatic groups of the ligands with Phe228 and Tyr132 prove to be most important for the differences in activity against C. albicans. In A. fumigatus there was a better occupation of the inner central I-spiral in the areas around the heme. For the activity against A. fumigatus the pi-pi interactions of aromatic groups of the compounds with Phe509, Phe228, and Tyr132 are significant for the activity.

A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID study of the species differences in the carcinogenicity of benzene derivatives chemicals

“…Further studies should be done to check these factors. For instance, one could use residues (not individual atoms) LBE as a descriptor calculated by molecular mechanics or other techniques [61].…”

“…Moreover, for some of the chemicals other oxidation positions in CYP2E1 are likely, producing additional metabolites that are important for carcinogenicity differences too; in some cases, as shown in our docking results, there were two different metabolites produced, which have almost equal quantities, in agreement to the experimental data. However, as we demonstrated recently, when the aim is to compare speciesrelated differences and identify the main ligand-receptor interaction, the use of docking conformers is not critical to obtain a sufficient match between 3D-QSAR, docking and LBE results [61]. Further help comes from 3D-QSAR and GRID maps comparison.…”

2D QSAR studies on a series of bifonazole derivatives with antifungal activity

“…5 Indeed, several three-dimensional quantitative structure-activity relationship studies (3D QSAR) have been reported for different datasets of azole derivatives 2,6,[9][10][11][12] however, this strategy afforded models with moderate robustness and local predictive ability only. For instance, Di Santo and co-workers 1 report that their CoMFA model was contradicted by the synthesis and evaluation of novel compounds.…”

Analysis of B-Raf $$^{\mathrm{V600E}}$$ V 600 E inhibitors using 2D and 3D-QSAR, molecular docking and pharmacophore studies

“…One of the wellestablished and widely used computational techniques in drug design is the quantitative structure-activity relationship (QSAR) method [22][23][24][25][26][27][28], in which the biological profiles of molecules can be derived based on chemical structural information [29][30][31][32][33][34]. Further improvements and developments of this method have led to the generation of the three-dimensional quantitative structure-activity relationship (3D-QSAR) method [35][36][37][38][39]. 3D-QSAR is widely used in drug design to study molecular features related to the improvement of the biological activity of newly designed inhibitors [26,[40][41][42].…”