Proline analogues are versatile chemical building blocks that enable modular construction of small-molecule drugs and pharmaceutical peptides. Over the past 15 years, the FDA has approved over 15 drugs containing proline analogues in their structures, five in the last three years alone (daridorexant, trofinetide, nirmatrelvir, rezafungin, danicopan). This perspective offers an analysis of the most common types of proline analogues currently trending in drug design. We focus on examples of fluoroprolines, α-methylproline, bicyclic proline analogues, and aminoprolines, while also highlighting proline analogues that remain underrepresented. We supplement our analysis with physicochemical information regarding the specific molecular properties of these moieties. Additionally, we discuss several intriguing cases where nonproline residues were replaced with proline analogues as a strategy to eliminate unwanted hydrogen bond donor sites. In conclusion, we present some suggestions for the future exploration of this promising class of molecular entities in drug discovery.

中文翻译：

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药物设计中的脯氨酸类似物：当前趋势和未来展望


脯氨酸类似物是多功能化学结构单元，可实现小分子药物和药物肽的模块化构建。在过去的 15 年里，FDA 已经批准了超过 15 种结构中含有脯氨酸类似物的药物，仅在过去三年中就有 5 种（daridorexant、trofinetide、nirmatrelvir、rezafungin、danicopan）。该观点分析了目前药物设计中最常见的脯氨酸类似物类型。我们重点介绍氟脯氨酸、α-甲基脯氨酸、双环脯氨酸类似物和氨基脯氨酸的例子，同时也重点介绍了代表性不足的脯氨酸类似物。我们用有关这些部分的特定分子性质的物理化学信息来补充我们的分析。此外，我们还讨论了几个有趣的案例，其中非脯氨酸残基被脯氨酸类似物取代，作为消除不需要的氢键供体位点的策略。总之，我们为未来在药物发现中探索这类有前途的分子实体提出了一些建议。