Spotlight on Target Engagement & Response
Allosteric Inhibitor for Abl Kinase
Researchers use HRPF to characterize allosteric inhibitors like GNF-5 for Abl kinase, revealing how binding induces conformational shifts that stabilize the inactive, closed state of the protein. Unlike traditional methods, HRPF also enables structural interrogation of intrinsically disordered regions (IDRs), which are difficult to study but play essential roles in kinase regulation, protein–protein interactions, and post-translational modifications. These insights are highly valuable in early-stage drug discovery, as they help researchers design more selective and effective small molecules, overcome resistance mechanisms, and reduce off-target effects, ultimately, accelerating the development of safer, next-generation therapeutics.
ATB Binding to Abl Kinase
Researchers use HRPF to study small molecule binding by mapping changes in solvent accessibility at the binding interface such as the ATP binding pocket of Abl kinase. In this study, HRPF revealed that ATP binding causes localized protection within the kinase domain, confirming site-specific interactions and capturing conformational effects not visible in static crystal structures. These results provide critical insight into how native ligands modulate protein structure and function, supporting structure-based drug design, validating binding specificity, and informing strategies to target conserved active sites in drug-resistant variants.
Small Molecule Binding
Researchers use HRPF to characterize small molecule interactions by mapping both direct binding sites and distal allosteric changes across the protein surface. In this study, three small molecules with a wide range of EC50 values (6 nM, 22 nM, and 900 nM) were compared, revealing distinct binding profiles and structural effects that correlate with potency. These insights help researchers understand structure–activity relationships (SAR), prioritize lead candidates, and design more effective therapeutics with improved specificity and fewer off-target effects. All critical steps in optimizing drug efficacy and safety.
