2026-09-16 バッファロー大学（UB）
University at Buffalo researchers have developed a drug molecule that causes its target protein to adapt to its shape.
＜関連情報＞
- https://www.buffalo.edu/news/releases/2026/09/drug-molecule-makes-square-peg-fit-round-hole.html
- https://onlinelibrary.wiley.com/doi/10.1002/anie.2953141
結合部位の枠にとらわれない発想：自己カプセル化キナーゼ阻害剤は、選択性を実現するために結合ポケットを再構築する Thinking Outside the Binding Site: A Self-Encapsulating Kinase Inhibitor Remodels Its Pocket to Achieve Selectivity
Nico J. Seidler, Monica R. MacDonald, Athina A. Moschopoulou, Sahba Cunningham, Tess M. Weber, Nader N. Nasief, Lorenz Mayer, Frederik W. Hacker, …
Angewandte Chemie International Edition Published: 15 September 2026
DOI:https://doi.org/10.1002/anie.2953141
ABSTRACT
Rendering kinase inhibitors selective is a strict requirement in drug development and remains a persistent challenge. To identify new routes to engineer selectivity, we have discovered a first-in-class p38δ-isoform selective inhibitor reflecting 12 000-fold selectivity improvement over currently available compounds and superior kinome targeting. X-ray crystallographic characterization indicates that these molecules bind through noncanonical n–π–π stacking sandwich interactions enabled by structural remodeling of the P-loop. Structural and functional analysis indicates that these selective inhibitors are self-encapsulating agents due to direct steric clashing that occludes the binding site in a conformation reinforced by a hydrogen-bonding network involving p38δ-unique H30. This work reveals how inhibitor selectivity is achieved by deliberate remodeling of the drug binding site leveraging structural features outside the binding site commonly overlooked in structure-guided design.
