Discovery of potential inhibitors for STAT3: Ligand based 3D
pharmacophore, Virtual Screening and Molecular Docking Studies
Abstract
Background: A tremendous research on signal transducer and activator of
transcription (STAT3) pertaining to cancer. It regulated the gene
expressions like normal cellular process includes differentiation, cell
development, proliferation, survival, maturation and immune perform.
There are many drugs are clinically approved derivatives are used as
STAT3 for cancer therapy suffer from many limitations related to
stability and toxicity. Experiment: In order to envisage structurally
diverse novel chemical entity as STAT3 poison with better efficacy,
Ligand-based-pharmacophore model was developed using 3D QSAR
pharmacophore generation (HypoGen algorithm) methodology in Discovery
studio 4.1 clients. The chemical features of 48 different derivatives
were taken as the training set. The selected pharmacophore model Hypo1
was further validated by 15 test set molecules and used as a query model
for further screening of 1,45,000 drug-like molecules from SPECS
databases. These molecules were subjected to several assessments such as
Lipinski rule of 5, verber’s rule and SMART filtration. The molecule
obtained after filtration was further scrutinized by molecular docking
analysis on the active site of STAT3 crystal structure. Result: 19
potential inhibitory molecules have been selected by analysing the
binding interaction and Ligand- Pharmacophore mapping with the validated
pharmacophore model. These 19 hits are further subjected to TOPKAT
program for toxicity assessment. These 19 hit molecules can be utilized
for designing future class of potential STAT3 inhibitor. Conclusion:
From the result of all of these studies compounds Specs 1, Specs 9,
Specs 13, Specs 17, Specs 28 and Specs 37 was finalised for further
studies.