Identification of novel small molecule TGF-β antagonists using structure-based drug design

Hao Wang, Richard B Sessions, Stephen S Prime, Deborah K Shoemark, Shelley J Allen-Birt, Wei Hong, Sathya Narayanan, Ian C Paterson

Research output: Contribution to journalArticle (Academic Journal)

6 Citations (Scopus)

Abstract

Aberrant transforming growth factor-β (TGF-β)
signalling has been associated with a number of disease
pathologies, such as the development of fibrosis in the
heart, lung and liver, cardiovascular disease and cancer,
hence the TGF-βpathway represents a promising target for
a variety of diseases. However, highly specific ways to
inhibit TGF-β signalling need to be developed to prevent
cross-talk with related receptors and minimise unwanted
side effects. We have used used virtual screening and
molecular docking to identify small molecule inhibitors of
TGF-β binding to TßRII. The crystal structure of TGF-β3
in complex with the extracellular domain of the type II
TGF-β receptor was taken as a starting point for molecular
docking and we developed a structure-based pharmacophore
model to identify compounds that competitively
inhibit the binding of TGF-β to TβRII and antogonize
TGF-β signalling. We have experimentally tested 67
molecules suggested by in silico screening and similarity
searching for their ability to inhibit TGF-b signalling in
TGF-β-dependent luciferase assays in vitro and the molecule
with the strongest inhibition had an IC50 of 18 lM.
These compounds were selected to bind to the SS1 subsite
(composed of F30, C31, D32, I50, T51 S52, I53, C54 and
E55) of TßRII and all share the general property of being
aromatic and fairly flat. Molecular dynamics simulations
confirmed that this was the most likely binding mode. The
computational methods used and the hits identified in this
study provide an excellent guide to medicinal chemistry
efforts to design tighter binding molecules to disrupt the
TGF-β/TßRII interaction.
Original languageEnglish
Pages (from-to)365-372
Number of pages8
JournalJournal of Computer Aided Design
Volume27
Issue number0920-654X
Early online date27 Apr 2013
DOIs
Publication statusPublished - 2013

Keywords

  • TGF-beta , Molecular docking

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