Pharmacophore Modeling, Docking and Molecular Dynamics Studies on Caspase-3 Activators Binding at β-Tubulin Site.

Abstract:

: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 protein-ligand complex.

authors

Bhunia SS,Singh S,Saxena S,Saxena AK

doi

10.2174/1573409911666150701103342

subject

Has Abstract

pub_date

2015-01-01 00:00:00

pages

72-83

issue

1

eissn

1573-4099

issn

1875-6697

pii

CCADD-EPUB-68434

journal_volume

11

pub_type

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