Src homology 2 (SH2) domains, modular units of 100 amino acids which recognize tyrosyl-phosphorylated peptide sequences on target receptor tyrosine kinases and other signaling proteins and bind to them, thus mediating intracellular protein-protein interactions, have been established to play a crucial role in various kinase-mediated intracellular signal transduction pathways.
Addressing this issue, our cheminformatics team has designed a new SH2 Domain Focused Library of 2,200 drug-like screening compounds with predicted affinity to SH2 domains, using a receptor-based approach: pharmacophore modeling based on X-ray data of SH2-inhibitor complexes.
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Background information
In general, over 110 human proteins contain SH2 domains, including kinases, transcription factors, and adaptor proteins. They are found in a wide variety of protein contexts, particularly in association with catalytic domains of phospholipase Cy (PLCy) and the non-receptor protein tyrosine kinases, in a group of small adaptor molecules (Crk and Nck), and within structural proteins, such as fodrin and tensin. Many of these proteins are overactivated in diseases (including cancer, diabetes, immune deficiency), and their functions depend highly on their SH2 domains.
Hence, disrupting the SH2 domain function in proteins to inhibit it is considered a promising way to develop novel therapeutic treatments. Despite the challenges associated with targeting the SH2 domain, the reported progress in the search for synthetic agents to fulfill the task has shown that such an approach in drug discovery has a confident future.
Compound selection
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.
As a result of applying 14 pharmacophore hypotheses, over 5,000 virtual screening hit compounds were revealed, with these compounds corresponding to 4 models (Fig. 1). After the manual inspection of the complexes and med/chem filtering, 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.
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