Development of Structure Activity Correlation Model on 4-Quinolones Derivatives as Tubulin Polymerization Inhibitors: Rationale to Advance the Understanding of Structure Activity Profile

Abstract

Three-dimensional quantitative structure-activity relationship (3D-QSAR), pharmacophore studies and docking studies was performed on a series of 4-Quinolones derivatives as antitumor agent and structure activity correlation was established. Subsequent ADME studies disclosed the pharmacokinetic efficiency of these compounds. 3D-QSAR models were generated using a set of 43 compounds of 4-Quinolones derivatives as inhibitor of tubulin polymerization for antitumor activity. Five-point common pharmacophore hypotheses were chosen for alignment of all compounds. The 3D-QSAR models generated using training set (31 compounds) and test set (12 compounds) exhibited good partial least squares statistical results. The developed common pharmacophore hypothesis (CPHs) and 3D-QSAR models were validated further externally by predicting the activity of database of compounds and comparing it with actual activity. We have selected the 3D-QSAR models generated by CPHs AADRR.11 for correlating the structure with activity. Docking studies were also performed for all compounds on colchicine binding site of β tubulin for examine the binding affinity of compounds for antitumor activity. ADME properties studies predict both physiochemically noteworthy descriptors and pharmacokinetically relevant properties extremely useful in the context of both high-throughput library screening and lead optimization. The results of these molecular modeling studies are helpful to improve the pharmacophore for design of novel potential compounds for antitumor activity.