Intervet Innovation GmbH, Schwabenheim, Germany.
Future Med Chem. 2011 Apr;3(6):699-708. doi: 10.4155/fmc.11.26.
The structure-based design of small-molecule inhibitors of protein-ligand and protein-protein interfaces is a key component of drug discovery. The underlying protein interactions can be regarded based on structural similarity of the secondary structure elements: similarities around the binding site ('ligand-sensing cores') or in the protein interface ('interface-sensing surfaces') in otherwise unrelated proteins can be useful in predicting polypharmacology and identifying new lead structures. Even small conserved motifs can provide similar interaction patterns in proteins with a completely different fold and function. The identification of these structural similarities can help in the design of new drugs by guiding further optimization. Here, the concepts and ideas based on secondary structure element similarities and their successful applications in drug design are reviewed and discussed.
基于结构的小分子抑制剂设计是药物发现的关键组成部分。基于二级结构元素的结构相似性，可以将潜在的蛋白质相互作用进行分类：在结合部位周围的相似性（“配体感应核心”）或在蛋白质界面中的相似性（“界面感应表面”）在原本不相关的蛋白质中可能有助于预测多药理学并确定新的先导结构。即使是小的保守基序也可以在具有完全不同折叠和功能的蛋白质中提供类似的相互作用模式。识别这些结构相似性可以通过指导进一步优化来帮助设计新药。在这里，我们回顾和讨论了基于二级结构元素相似性的概念和想法及其在药物设计中的成功应用。
