Day Two

As the toolbox of techniques and modalities continues to expand, structure-based drug design is at a crossroads. This interactive panel invites the audience and expert panellists to reflect on the most pressing challenges, biggest opportunities, and future directions to maximize the impact of structural insights on drug discovery.

Key Discussion Points:

• What are the key bottlenecks still limiting the impact of SBDD (resolution, dynamics, integration, translation to clinic)?
• Which emerging tools (AI, cryo-ET, integrative modelling, real-time structural methods) will reshape the field in the next 5 years?
• How can we bridge the gap between structural data and actionable design decisions for both small molecules and biologics?
• What collaborations, technologies, or standards are still needed to make SBDD more predictive and accessible?

• Explore structure-guided strategies to engineer antibodies and biologics that move beyond passive binding to actively modulate biological pathways
• Leverage structural insights to optimize stability, specificity, and functionality across complex or traditionally intractable targets
• Discuss emerging design principles and case studies showcasing functional biologics with enhanced therapeutic potential

• Reveal high-resolution cryo-EM structures of the DCAF2:DDB1:DDA1 complex to elucidate ligand binding and substrate recruitment mechanisms
• Demonstrate covalent fragment engagement of C141 and degrader-mediated ternary complex formation driving BRD4 ubiquitination and degradation
• Discuss how structural and functional validation of DCAF2 expands the usable E3 ligase repertoire for next-generation molecular glue and degrader design

• Moving beyond selection toward design-first approaches for novel antibodies and biologics
• Using AI-guided structural prediction to identify new binding sites and functional epitopes
• Designing antibodies with targeted MOAs: activation, switching, signalling
• Integrating AI models with experimental validation to accelerate biologic discovery pipelines

• First high-resolution structure of a human transcription factor–BAF complex revealed, mapping the PU.1–BAF binding interface
• Biochemical studies define the molecular determinants of PU.1–BAF interaction, a key driver in lineage-specific transcription
• Identification of potential small-molecule inhibitors offers a new therapeutic strategy to disrupt aberrant TF–BAF activity in cancer

• Apply X-ray crystallography, Cryo-EM, and proteomics to elucidate neosubstrate recruitment, neomorphic interactions, and degradative mechanisms
• Showcase structure-guided and computationally driven design of molecular glues and PROTACs to expand the druggable target space
• Characterize transient and low-affinity ternary complexes to understand cooperativity, conformational plasticity, and multi-domain binding modes
• Integrate structural insights with predictive modeling to stabilize complexes and overcome translational barriers in next-generation TPD therapeutics

• Dissecting GLP-1 conformational states with small molecule ligands to map downstream pharmacological effects
• Accelerating insights through advanced computational and data-driven approaches
• Translating structural and computational findings into actionable guidance for medicinal chemistry efforts

• Unveiling the cryo-EM structures of Polθ helicase bound to DNA and how structural rearrangements facilitate error-prone double-strand break repair
• Positioning 3′ single-stranded DNA ends to align complementary bases
• Highlighting structural determinants and potential allosteric sites for therapeutic intervention
• How structure-guided drug discovery is advancing first-in-class Polθ inhibitors to address DNA repair vulnerabilities in cancer

Exploring the unique hurdles of designing drugs for RNA, PROTACs, and beyond. Panellists will discuss structural and physicochemical challenges, computational and biophysical tool limitations, permeability and delivery barriers, and the need for novel screening and optimization strategies to unlock these emerging therapeutic modalities.

Discussion Points:

• What structural and physicochemical features make RNA, macrocycles, and PROTACs especially challenging compared to small molecules?
• How can computational chemistry, structural biology, and biophysics be adapted to better interrogate these modalities?
• What strategies are most promising for improving permeability, stability, and delivery of large or complex molecules?
• How can we build robust optimization workflows to balance potency, selectivity, and drug-like properties across different modalities?