2D- and 3D-QSAR Study of Acyl Homoserine Lactone Derivatives as Potent Inhibitors of Quorum Sensor, SdiA in Salmonella typhimurium

Abstract

A series of Acyl homoserine lactone derivatives against quorum sensing (QS) enhanced transcriptional regulator SdiA of S. typhimurium were used to establish the physicochemical and structural requirements for the inhibition of QS using 2D- and 3D-QSAR methods. The QSAR model was developed by employing 35 compounds as a training set and the predictive ability was assessed by a test set of 12 compounds. The best 2D-QSAR model for the prediction of SdiA, quorum sensor inhibitory activity has been developed using Multiple Linear Regression method (giving r2 = 0.8012 and q2 = 0.657), Principal Component Regression method (giving r2 = 0.8104 and q2 = 0.625), and Partial Least Squares Regression method (giving r2 = 0.8023 and q2 = 0.648). The best model for 3D-QSAR has been obtained using Comparative Molecular Field Analysis (CoMFA) method, giving r2 = 0.896 and q2 = 0.772. The 2D-QSAR results revealed that the most important descriptors for predicting the anti-quorum sensing activity were alignment-independent descriptors and the topology index descriptors. The 3D-QSAR results of CoMFA contour maps impart some important structural features-like electronegative substituent (Br, Cl, F) on lactone ring favors the strong inhibitory activity. These results will be further useful for development of new quorum sensing inhibitors with structural diversity.

Keywords

• Salmonella typhimurium
• 2D-QSAR
• 3D-QSAR
• CoMFA
• QS inhibitors