Title:Development of Structure Activity Correlation Model on Azetidin-2-ones as Tubulin Polymerization Inhibitors
VOLUME: 12 ISSUE: 5
Author(s):Vijay Kumar Patel, Kavibhushan Singh Chouhan, Avineesh Singh, Deepak Kumar Jain, Ravichandran Veerasamy, Pradeep Kumar. Singour, Rajesh Singh Pawar and Harish Rajak
Affiliation:Medicinal Chemistry Research Laboratory, SLT Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur-495 009 (CG) India.
Keywords:Anticancer activity, azetidin-2-ones, structure and ligand based method, structure activity correlation, tubulin polymerization
inhibitors.
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.
