Pharmacophore Modeling, Docking and Molecular Dynamics Studies on Caspase-3 Activators Binding at β-Tubulin Site
Shome S. Bhunia,
Anil K. Saxena.
Induction of apoptosis by the activation of caspase 3 makes it a promising target for
designing anticancer drugs hence an investigation for the essential structural features mandatory for
caspase 3 activation has been carried out using a dataset comprising of caspase 3 activator candidate
drug Azixa in phase II clinical trial and its analogs using DS2.0. A training set of 40 compounds was
selected for the purpose of model generation from 76 molecules with an activity range spanning from 0.002μM to 6.9μM.
Among the generated pharmacophore models, the best model Hypo1 constituted by two hydrophobic aliphatic (Hal), two
hydrophobic aromatic (Har), and one hydrogen bond acceptor (HBA) features with a correlation coefficient of 0.85, and a
cost difference (null cost – total cost) of 46 bits well predicted the test set of 36 compounds (Rpred = 0.8). The key
mechanism conferring caspase 3 activation is due to binding of Azixa at β-tubulin site that is located close to or at same
site as colchicine. In the absence of co-crystal structure we have proposed a binding mode of Azixa at the tubulin site by
performing docking studies and performed molecular dynamics simulation to ascertain the temporal changes of the
Keywords: Caspase 3 activation, pharmacophore azixa, docking azixa, quinazoline pharmacophore.
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