Molecular modeling studies of substituted 3,4-dihydroxychalcone derivatives as 5-lipoxygenase and cyclooxygenase inhibitors

Abstract

A fifty-four compound series of 5-lipoxygenase and cyclooxygenase inhibitory activity of substituted 3,4-dihydroxychalcones was subjected to the development of a robust quantitative structure–activity relationship (QSAR) and pharmacophore model and the investigation of structure–activity relationship analysis using Molecular Design Suite software version 3.5. The requirements for the 5-lipoxygenase and cyclooxygenase activity are explored with 2D, group based and k-Nearest Neighbor studies. Simulated annealing is applied as variable selection methods for an effective comparison and model development. Several statistical expressions were developed using partial least square (PLS) analysis. The best QSAR models were further validated by leave-one-out method of cross-validation. The statistically significant best 2D-QSAR model was selected, having correlation coefficient r2 = 0.9338, and cross-validated squared correlation coefficient q2 = 0.7832 with external predictive ability of pred_r2 = 0.8169 was developed by simulated annealing PLS with the descriptors like Average −ve potential, SsCH3E-index, SsClE-index, SsOH count, and HUMO Energy. Group based QSAR model indicates that molar refractivity and methoxy, ethoxy, carboxylic groups in R1 positions can enhance activity. The obtained 3D-QSAR (k-Nearest Neighbor) model using simulated annealing as a variable selection method has an excellent correlation coefficient value (r2 = 0.8537) along with good statistical significance as shown by high Fisher’s ratio (F = 73.86). The model also exhibits good predictive power confirmed by the high value of cross-validated correlation coefficient (q2 = 0.7841). The k-Nearest Neighbor contour maps suggest some important structural features like electronegative substituents which are essential for the activity exhibited by these compounds, and inclusion of electron-donating substituents will enhance the 5-lipoxygenase and cyclooxygenase inhibition activity. The pharmacophore analysis of the molecules demonstrated that the aromatic/aliphatic and hydrogen bond donor features are important pharmacophore contours favorable for these activities. The information rendered by 2D-QSAR, group based and 3D-QSAR models may lead to a better understanding of structural requirements of chalcone derivatives and also aid in designing novel potent 5-lipoxygenase and cyclooxygenase molecules.