导 读
近日美国学者报道利用硼酸易形成氢键的特点，设计了一种亲和力极好的HIV-1蛋白抑制剂。相关研究发表于Journal of the American Chemical Society，题为“Sub-Picomolar Inhibition of HIV-1 Protease with a Boronic Acid”。
研究背景
临床使用的HIV-1蛋白酶抑制剂是基于结构的药物设计的典型胜利。针对酶S2亚位点的双THF结构的发现（Darunavir）是一个重大突破，两个四氢呋喃环上的氧原子作为Asp29和Asp30的氢键受体。
结果速览
监测底物和Darunavir类似物结合的络合物的结构告诉我们，半数内源底物利用谷氨酰胺或谷氨酸残基占据S2，亚位点。
通过对分子对接的研究，他们认为靶向S2，亚位点的官能团应该是既有氢键受体又有氢键给体，考虑到硼酸中的两个羟基提供4个孤对电子和两个氢键受体，设计了Darunavir的4-磺酰苯胺部分被4-磺基苯基硼酸取代的一个硼酸化合物。
硼酸被认为是共价络合的主要成分，很少被用作非共价识别的试剂。利用硼酸基团形成氢键的能力，它们开发了一种具有极强亲和力的HIV-1蛋白酶抑制剂。具体来说，它们发现苯硼酸取代的Darunavir比Darunavir对蛋白酶的亲和力提高了20倍。X射线衍射表明，硼酸基团参与了三个氢键，超过了达鲁那韦的氨基或其他类似物。重要的是，硼酸保持它的氢键和它对耐药的HIV-1蛋白酶的D30N变异体的亲和力。硼酸和Asp之间的BOH···OC氢键较短(rO···O=2.2)，密度泛函理论分析表明它们具有较高的共价性。这些数据表明了硼酸作为多功能基团在小分子配体设计中的实用性。
ABSTRACT
Boronic acids have been typecast as moieties for covalent complexation and are employed only rarely as agents for noncovalent 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, exceeding that of 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 (rO···O = 2.2 ), 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.
原文链接：
https://pubs.acs.org/doi/10.1021/jacs.8b07366
本期编辑：碳硼酸
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