15 research outputs found
Binding Modes of Peptidomimetics Designed to Inhibit STAT3
STAT3 is a transcription factor that has been found to be constitutively activated in a number of human cancers.
Dimerization of STAT3 via its SH2 domain and the subsequent translocation of the dimer to the nucleus leads to
transcription of anti-apoptotic genes. Prevention of the dimerization is thus an attractive strategy for inhibiting the activity
of STAT3. Phosphotyrosine-based peptidomimetic inhibitors, which mimic pTyr-Xaa-Yaa-Gln motif and have strong to weak
binding affinities, have been previously investigated. It is well-known that structures of protein-inhibitor complexes are
important for understanding the binding interactions and designing stronger inhibitors. Experimental structures of
inhibitors bound to the SH2 domain of STAT3 are, however, unavailable. In this paper we describe a computational study
that combined molecular docking and molecular dynamics to model structures of 12 peptidomimetic inhibitors bound to
the SH2 domain of STAT3. A detailed analysis of the modeled structures was performed to evaluate the characteristics of the
binding interactions. We also estimated the binding affinities of the inhibitors by combining MMPB/GBSA-based energies
and entropic cost of binding. The estimated affinities correlate strongly with the experimentally obtained affinities.
Modeling results show binding modes that are consistent with limited previous modeling studies on binding interactions
involving the SH2 domain and phosphotyrosine(pTyr)-based inhibitors. We also discovered a stable novel binding mode
that involves deformation of two loops of the SH2 domain that subsequently bury the C-terminal end of one of the stronger
inhibitors. The novel binding mode could prove useful for developing more potent inhibitors aimed at preventing
dimerization of cancer target protein STAT3