Abstract
Structure and ligand based approaches are effectively employed for the accurate design of ligands. The main objective of this study was to find out the correlation between structure and biological activity using structure and ligand based methodology. Azetidin-2-ones have been recognized as effective tubulin polymerization inhibitors that bind to the colchicine site on β-tubulin. Molecular docking (structure based method) was performed on a series of azetidin-2-ones using colchicines binding β tubulin. The docking studies indicate the important interactions of trimethoxy benzene with Cys241 and Val318 for anticancer activity. Energetic based pharmacophore mapping (hybrid structure and ligand based method) explain how the energy parameter from the Glide XP scoring function are plotted onto pharmacophore sites from the docked fragments so as to rank their implication for binding. Pharmacophore and atom based 3D QSAR modeling (ligand based method) was performed on 71 compounds of azetidin-2-ones derivatives as tubulin-binding agents for antitumor activity. Five-point common pharmacophore hypothesis was selected for alignment of all compounds. The 3D-QSAR models were developed using training set of 51 compounds and test set of 20 compounds. The generated common pharmacophore hypothesis (CPHs) and 3D-QSAR models were confirmed further externally by estimating the activity of database of compounds and comparing it with actual activity. We have established structure activity correlation using docking, energetic based pharmacophore mapping, pharmacophore and atom based 3D QSAR model. The results of these studies would be beneficial to refine the pharmacophore for design of novel potential compounds for antitumor activity.
Keywords: Anticancer activity, azetidin-2-ones, structure and ligand based method, structure activity correlation, tubulin polymerization inhibitors.
Graphical Abstract
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