Identification of new GATA4-small molecule inhibitors by structure-based virtual screening.

Abstract:

:Members of the GATA family of transcription factors are zinc finger proteins that were shown to play evolutionary conserved roles in cell differentiation and proliferation in different organisms. We hypothesized that by finding new molecules that inhibit their function to be crucial in future therapeutical interventions for various diseases. By virtual high throughput screening using a version of glide (Schrodinger®) program with both crystal and NMR structure of GATA C-terminal zinc finger, we identified new small molecular weight chemicals with lead-like properties. We used in vitro cell-based assays to show that these molecules selectively and efficiently inhibit GATA4 activity by inhibiting its interaction with the DNA. In addition we showed that these molecules can block the activation of downstream target genes by GATA4. Moreover these compounds can moderately enhanced a mouse model of myoblast differentiation into myotubes. This might be partially due to decreased GATA4/DNA interaction as shown by gel retardation assays. Further investigation is needed to reach selectivity and efficacy. Our study however do show that in silico screening combined with in vitro studies are efficient tools to unravel new molecules that interact with zinc finger proteins such as GATA4.

journal_name

Bioorg Med Chem

authors

El-Hachem N,Nemer G

doi

10.1016/j.bmc.2011.01.022

subject

Has Abstract

pub_date

2011-03-01 00:00:00

pages

1734-42

issue

5

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(11)00038-1

journal_volume

19

pub_type

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