It is known that Src homology 2 (SH2) domains are modular units of 100 amino acids that recognize and bind to tyrosyl-phosphorylated peptide sequences on target receptor tyrosine kinases and other signaling proteins, mediating intracellular protein-protein interactions. They play key roles in various kinase-mediated intracellular signal transduction pathways.
The studies of the clinical relevance of targeting SH2 domains have made substantial progress, thus stimulating the development of synthetic agents that disrupt the SH2 domain function in proteins.
Over 110 human proteins contain SH2 domains, including kinases, transcription factors, and adaptor proteins. Many of these proteins are overactivated in diseases (including cancer, diabetes, immune deficiency), and their functions are highly dependent on their SH2 domains. Hence, disrupting the SH2 domain of proteins to inhibit their function has emerged as a promising method for developing novel therapeutic treatments. Despite the challenges associated with targeting the SH2 domain, the progress reported so far shows that such an approach in drug discovery is full of promise.
The SH2 Domain Focused Library of 2,200 drug-like screening compounds with predicted affinity to SH2 domains available from Life Chemicals has been designed with a receptor-based approach: pharmacophore modeling using X-ray data of SH2-inhibitor complexes.
Initially, all available X-ray structures of SH2 domains complexed with a small-molecule inhibitor (157 total) were obtained from the Protein Data Bank and narrowed down to 63 structures by manual inspection. Then, after diversity analysis and discarding the most similar structures by molecular clustering, 14 3D pharmacophore models were generated and screened against the Life Chemicals HTS Compound Collection. Besides the ligand pharmacophore features, the models included SH2 domain excluded volumes that represent its structure. As a result of applying 14 pharmacophore hypotheses, over 5,000 virtual screening hit compounds were revealed with 4 models (Fig. 1). After the manual inspection of the complexes and med/chem filters applied, 2,200 best-scored and structurally diverse potential SH2 inhibitors were included in the focused library. The SH2 Domain Screening Compound Library does not contain PAINS, toxic and reactive compounds, however, Ro5 criteria were omitted since many SH2 inhibitors are peptides.
Cherry-picking is available. Custom compound selection based on specific parameters can be performed on request.
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Figure 1. SH2 pharmacophore models and their respective matches from the SH2 focused library. The models were generated based on the complex of the SH2 domain with various ligands (X-ray data). A: 1O4H B: 1O4I C: 1IJR D: 1O4A