Department of Chemistry , Massachusetts Institute of Technology , Cambridge , Massachusetts 02139 , United States.
J Am Chem Soc. 2018 Oct 31;140(43):14015-14018. doi: 10.1021/jacs.8b07366. Epub 2018 Oct 22.
Boronic acids have been typecast as moieties for covalent complexation and are employed only rarely as agents for non-covalent recognition. By exploiting the profuse ability of a boronic acid group to form hydrogen bonds, we have developed an inhibitor of HIV-1 protease with extraordinary affinity. Specifically, we find that replacing an aniline moiety in darunavir with a phenylboronic acid leads to 20-fold greater affinity for the protease. X-ray crystallography demonstrates that the boronic acid group participates in three hydrogen bonds, more than the amino group of darunavir or any other analog. Importantly, the boronic acid maintains its hydrogen bonds and its affinity for the drug-resistant D30N variant of HIV-1 protease. The BOH···OC hydrogen bonds between the boronic acid hydroxy group and Asp30 (or Asn30) of the protease are short ( r = 2.2 Å), and density functional theory analysis reveals a high degree of covalency. These data highlight the utility of boronic acids as versatile functional groups in the design of small-molecule ligands.
硼酸已被定型为共价络合的部分，并且很少作为非共价识别的试剂使用。通过利用硼酸基团形成氢键的丰富能力，我们开发出了一种具有非凡亲和力的 HIV-1 蛋白酶抑制剂。具体来说，我们发现用苯硼酸取代达鲁那韦中的苯胺部分会导致对蛋白酶的亲和力增加 20 倍。X 射线晶体学表明，硼酸基团参与了三个氢键，超过了达鲁那韦的氨基或任何其他类似物。重要的是，硼酸保持其氢键和对 HIV-1 蛋白酶耐药 D30N 变体的亲和力。硼酸羟基与蛋白酶的 Asp30（或 Asn30）之间的 BOH···OC 氢键较短（r = 2.2 Å），密度泛函理论分析显示出高度的共价性。这些数据突出了硼酸作为小分子配体设计中多功能官能团的实用性。
