Developing small-molecule drugs for hard-to-drug targets remains one of the toughest challenges in modern drug discovery. Targets like cytokines, transcription factors, and scaffolding proteins often lack well-defined binding pockets, making it difficult to design inhibitors with effective binding capabilities. These proteins usually interact through large, flat protein-protein interfaces, requiring innovative methods to identify potential small-molecule binders.
Our team recently confronted this challenge by focusing on a single cytokine target and employing three complementary biophysical modalities: Surface Plasmon Resonance (SPR), Target-Immobilized NMR Screening (TINS), and DNA Encoded Library (DEL) screening. This integrated approach allowed us to explore the binding landscape from multiple perspectives, ensuring no potential hits were missed.
Each technique played a crucial role in our comprehensive analysis. SPR excelled at identifying fragments with strong, measurable affinity and provides kinetics, while TINS uncovers weaker interactions that SPR might overlook, providing alternative starting points for fragment elaboration. The DEL screen extended the chemical space to larger molecules, revealing unique chemotypes that complemented the smaller hits identified through SPR and TINS. Together, these methods formed a powerful toolkit for addressing even the most challenging drug targets.
This multi-modal strategy highlights the value of combining complementary techniques in drug discovery. By leveraging the distinct strengths of SPR, TINS, and DEL screening, we assembled a diverse and robust portfolio of hits for further validation and optimization.
Looking further down the line, we will move the projects into structural biology using techniques such as X-ray crystallography, NMR or cryo-EM to visualize binding modes. Additionally, fluorescence-based assays and other biophysical methods are used as orthogonal validation of the most promising hits.
Stay tuned for updates as we continue to explore innovative solutions to some of the toughest challenges in drug development!