科研之友
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摘要
Quantitative structure-activity relationship (QSAR) and Pharmacophore studies were performed on a series of 35 azaaurones derivatives to find out the structural requirements of their antimalarial activities. The compounds in the selected series were characterized by spatial, molecular and electrotopological descriptors using QSAR module of molecular design suite (V-Life MDSTM 3.5). Correlations between inhibitory activities and calculated predictor variables were established through partial least square regression method. The developed QSAR models were found to be statistically significant with respect to training (r (2) > 0.6), and cross-validation (q (2) > 0.6). Simulated annealing (SA) and stepwise (SW) regression are applied as variable selection methods for an effective comparison and model development. This study was performed with 35 compounds (data set) using the sphere exclusion (SE) algorithm method for the division of the data set into training and test sets. The statistically significant 2D-QSAR model having r (2) = 0.9061 and q (2) = 0.8150 with pred_r (2) = 0.8719 was developed by SW-PLS confirms a positive contribution of T_O_Cl_6, T_C_Cl_1, SsOHcount, T_C_F_2 and SsCH(3)E index to the anti-malarial activity and best Group-based QSAR (GQSAR) model having r (2) = 0.7624 and q (2) = 0.7341 with pred_r (2) = 0.7461 was developed by SA-PLS. The result two-dimensional QSAR and GQSAR clearly explained that substitution of topological indices, hydrophobic properties and auto-correlation descriptors of different atomic properties at R1 and R2 on aurone ring is essential for the activity. Further analysis using three-dimensional QSAR technique identifies a suitable model obtained by SA-partial least square method leading to anti-malarial activity prediction. Molecular field analysis was used to construct the best 3D-QSAR model using k-nearest neighbor method, showing good correlative and predictive capabilities in terms of q (2) = 0.6906 and pred_r (2) = 0.7454. Additionally the pharmacophore model well corroborated with k-nearest neighbor studies as the contours of later were in good agreement with the 3D orientation of the pharmacophoric features. The distances between the pharmacophore sites were measured in order to confirm their significance to the activities. The results reveal that the acceptor, donor, and aromatic/hydrophobic pharmacophore properties are favorable contours sites for the activities. The results of 2D-QSAR, GQSAR and k-nearest neighbor-based 3D-QSAR studies give detailed structural insights as well as highlights important binding features of these substituted azaaurones derivatives as anti-malarial activity, which can provide guidance for the rational design of novel potent azaaurones derivatives.
- 出版日期2014-1
