Molecular modeling and pharmacophore approach for structural requirements of some 2-substituted-1-naphthols derivatives as potent 5-lipoxygenase inhibitors

Abstract

Molecular modeling and pharmacophore study has been performed on a series of 2-Substituted-1-naphthols derivatives with potent 5-lipoxygenase inhibitory activity. Structural features responsible for the activity of the compounds were characterized by using physicochemical, topological, and electrotopological descriptors, calculated from the Molecular Design Suite Software (V-life MDS™ 3.5). The relationship developed between biological activity and electrostatic, steric, hydrophobicity parameters was explored to generate combinatorial library with various substitution. This library can be explored for the synthesis and study of future potential anti-inflammatory agent. The requirements for the 5-lipoxygenase inhibitory activity are explored with 2D-QSAR, group based QSAR (G-QSAR), and k-nearest neighbour studies. The statistically significant 2D-QSAR model having r 2 = 0.8502 and q 2 = 0.8144 with pred_r 2 = 0.8072 and the best group based QSAR (G-QSAR) model having r 2 = 0.9137 and q 2 = 0.7808 with pred_r 2 = 0.8490 was developed by simulated annealing based partial least squares method. Further analysis using k-nearest neighbour 3D-QSAR technique identifies two models obtained by simulated annealing (SA) and genetic algorithm (GA)-based partial least squares methods leading to 5-lipoxygenase activity prediction. The best simulated annealing QSAR model showed q 2 = 0.8547, r 2 = 0.8963, and standard error = 0.3677. It was observed that steric properties predicted by k-nearest neighbour MFA contours can be related to 5-lipoxygenase activity. The predictive ability of the resultant model was evaluated using a test set molecules and the predicted r 2 = 0.8162. The best pharmacophore model with hydrophobic, hydrogen bond donor (HBD), and aromatic features has root mean square deviation (RMSD) of 0.5746. The QSAR model suggests that electron-withdrawing character is favorable for the 5-lipoxygenase inhibitory activity. This suggests that electron-withdrawing groups like a chlorine or fluorine atoms at naphthol moiety are good for anti-inflammatory activity. In addition to the electron-withdrawing character, electron-donating groups, hydrophobic and hydrogen bond donor groups positively contribute to the 5-lipoxygenase inhibition. The results of 2D-QSAR, Group based QSAR, and k-nearest neighbour 3D-QSAR studies give detailed structural insights as well as highlights important binding features of these 2-Substituted-1-naphthols derivatives as anti-inflammatory agents which can provide guidance for the rational design of novel potent 5-lipoxygenase inhibitors.