Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, 100 Binney Street, Cambridge, MA 02142, USA.
Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, NJ 08543-4000, USA.
Bioorg Med Chem Lett. 2022 Nov 1;75:128983. doi: 10.1016/j.bmcl.2022.128983. Epub 2022 Sep 9.
The cyclic structure of proline (Pro) confers unique conformational properties on this natural amino acid that influences polypeptide structure and function. Pseudoprolines are a family of Pro isosteres that incorporate a heteroatom, most prominently oxygen or sulfur but also silicon and selenium, to replace the C or C carbon atom of the pyrrolidine ring. These readily synthetically accessible structural motifs can facilitate facile molecular editing in a fashion that allows modulation of the amide bond topology of dipeptide elements and influence over ring pucker. While the properties of pseudoprolines have been exploited most prominently in the design of oligopeptide analogues, they have potential application in the design and optimization of small molecules. In this Digest, we summarize the physicochemical properties of pseudoprolines and illustrate their potential in drug discovery by surveying examples of applications in the design of bioactive molecules.
脯氨酸（Pro）的环状结构赋予了这种天然氨基酸独特的构象特性，从而影响多肽的结构和功能。假脯氨酸是脯氨酸的等排体家族，其中包含一个杂原子，最常见的是氧或硫，但也有硅和硒，取代吡咯烷环的 C 或 C 碳原子。这些易于合成的结构基序可以促进分子编辑，从而调节二肽元件中酰胺键的拓扑结构，并影响环的构象。虽然假脯氨酸的性质在寡肽类似物的设计中得到了最突出的应用，但它们在小分子的设计和优化中具有潜在的应用。在这篇综述中，我们总结了假脯氨酸的物理化学性质，并通过调查生物活性分子设计中应用的实例来说明它们在药物发现中的应用潜力。
