Virtual fragmentation of a library of 12,000 compounds inspired by natural products led to a dataset of 153,000 fragments that was used as a source to identify effective P2-P3 scaffold replacement solutions for peptidic Caspase-1 inhibitors. Our strategy led to the identification of an original 2-azabicyclo-octane scaffold (2-ABO) that was further elaborated into the potent Caspase-1 inhibitor CD10847 (IC₅₀ = 17 nM). The crystal structure of Caspase-1 in complex with CD10847 was obtained, and its binding mode was shown to be similar to the one predicted by docking and in good agreement with other known inhibitors.

由天然产物激发的12,000个化合物的库的虚拟片段化导致了153,000个片段的数据集，该数据集被用作鉴定肽类Caspase-1抑制剂的有效P2-P3支架替代溶液的来源。我们的策略导致鉴定出原始的2-氮杂双环辛烷骨架（2-ABO），该骨架进一步制成有效的Caspase-1抑制剂CD10847（IC ₅₀  = 17 nM）。获得了与CD10847复合的Caspase-1的晶体结构，其结合模式显示出与通过对接预测的模式相似，并且与其他已知的抑制剂有很好的一致性。