Abstract
We present a new approach for the identification of inhibitors of phosphorylation‐dependent protein–protein interaction domains, in which phenolic fragments are adapted by in silico O‐phosphorylation before docking‐based screening. From a database of 10 369 180 compounds, we identified 85 021 natural product‐derived phenolic fragments, which were virtually O‐phosphorylated and screened for in silico binding to the STAT3 SH2 domain. Nine screening hits were then synthesized, eight of which showed a degree of in vitro inhibition of STAT3. After analysis of its selectivity profile, the most potent inhibitor was then developed to Stafia‐1, the first small molecule shown to preferentially inhibit the STAT family member STAT5a over the close homologue STAT5b. A phosphonate prodrug based on Stafia‐1 inhibited STAT5a with selectivity over STAT5b in human leukemia cells, providing the first demonstration of selective in vitro and intracellular inhibition of STAT5a by a small‐molecule inhibitor.
Highlights
We present a new approach for the identification of inhibitors of phosphorylation-dependent protein– protein interaction domains, in which phenolic fragments are adapted by in silico O-phosphorylation before docking-based screening
We recently proposed O-phosphorylation of preselected natural products as an approach for the development of non-peptidic and non-reactive ligands of phosphorylation-dependent protein–protein interactions.[3]
The initial virtual compound library was downloaded from the ZINC database[11] as a collection of 10 369 180 structures. Filtering this database for structural elements described by the structural classification of natural products (SCONP) tree[10] identified 799 335 compounds (Figure 1 A, step 1, Figure S1, and Supporting Methods in the Supporting Information)
Summary
We present a new approach for the identification of inhibitors of phosphorylation-dependent protein– protein interaction domains, in which phenolic fragments are adapted by in silico O-phosphorylation before docking-based screening. Phosphorylation-dependent protein–protein interactions are mediated by the phosphorylated side chains of tyrosine, serine, and threonine residues, and play an important role in signal transduction.
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