ChemDiv’s library of small molecules targeting Src Homology 2 domains contains 12,000 compounds
Src homology 2 (SH2) domains are modular units comprising approximately 100 amino acids that specifically recognize and bind to tyrosine-phosphorylated peptide sequences on target proteins, thereby facilitating intracellular protein-protein interactions.
SH2 domains play a pivotal role in cellular signaling pathways that regulate a variety of physiological processes, including cell growth, differentiation, migration, and apoptosis. These domains serve as critical mediators of intracellular protein-protein interactions. By selectively interacting with phosphorylated tyrosine residues, SH2 domains facilitate the assembly of signaling complexes at precise cellular locations, thereby ensuring accurate signal transduction in response to external or internal stimuli. This specificity and versatility make SH2 domains integral components in the signaling pathways that govern immune responses, cell cycle progression, and cellular metabolism, highlighting their significance in maintaining cellular homeostasis and function.
From a drug discovery perspective, the ability of SH2 domains to modulate key signaling pathways presents a valuable opportunity for therapeutic intervention. Aberrant SH2 domain activity is often linked to the pathogenesis of various diseases, including cancers, autoimmune disorders, and inflammatory conditions, where dysregulated signal transduction contributes to disease progression. Targeting SH2 domains with small molecule inhibitors or modulators can potentially restore normal signaling dynamics, offering a strategic approach to counteract the pathological overactivation or inhibition of critical signaling pathways. The specificity of SH2 domain interactions also allows for the development of targeted therapies that minimize off-target effects, enhancing therapeutic efficacy and patient safety. Consequently, understanding the physiological roles and mechanisms of SH2 domains not only advances our knowledge of cellular signaling processes but also opens new avenues for designing innovative treatments for complex diseases.
To date, over 50 crystallographic complexes of small-molecule SH2 domain inhibitors have been documented in the Protein Data Bank (PDB). A four-centered pharmacophore model was developed based on selected X-ray data (PDB IDs: 2WKM, 3GQL, and 4AOI). Reference compounds were subsequently docked into this model starting from their 2D structures, without stereochemical assignments. The docking results showed a good correlation with the referenced solution activity (average RMSD = 0.2).
All compounds from the SH2 domain library were assessed using this pharmacophore model. Molecules scoring highly were incorporated into the library, constituting more than 50% of the total collection. This approach enhances the library's relevance for discovering effective SH2 domain inhibitors, underscoring the utility of combining crystallographic insights with pharmacophore modeling in drug discovery.