Contribution of fluorine to protein-ligand affinity in the binding of fluoroaromatic inhibitors to carbonic anhydrase II
Contribution of fluorine to protein-ligand affinity in the binding of fluoroaromatic inhibitors to carbonic anhydrase II
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DOI：
10.1021/ja002627n
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发表时间：
2000-12-13
影响因子：
15
通讯作者：
Christianson, DW
中科院分区：
文献类型：
--
作者：
Kim, CY;Chang, JS;Christianson, DW
碳酸酐酶 II (CAII) 是一种锌金属酶，可催化 CO2 水合产生碳酸氢根和质子。 N-(4-磺酰基苯甲酰基)苯甲胺 (SBB) 是人 CAII 的紧密结合抑制剂，K-d = 2.1 nM。之前的X射线晶体学工作表明，SBB的苄基环与酶活性位点的Phe-131发生边对面相互作用。我们通过系统地用带负电的氟原子取代 SBB 的苄基环氢来操纵这种相互作用的静电。 10 种酶-抑制剂复合物的晶体结构已确定至原子分辨率。对这些结构的分析表明，对酶-抑制剂亲和力的主要贡献可以通过偶极诱导偶极、偶极-四极和四极-四极相互作用的组合来近似。令人惊讶的是，不同的静电成分在不同的酶-抑制剂对中主导着亲和力。
Carbonic anhydrase II (CAII) is a zinc metalloenzyme that catalyzes the hydration of CO2 to yield bicarbonate and a proton. N-(4-Sulfamylbenzoyl)benzylamine (SBB) is a tight-binding inhibitor of human CAII with K-d = 2.1 nM. Previous X-ray crystallographic work shows that the benzyl ring of SBB makes an edge-to-face interaction with Phe-131 in the enzyme active site. We have manipulated the electrostatics of this interaction by systematically substituting electronegative fluorine atoms for the benzyl ring hydrogens of SBB. Crystal structures of 10 enzyme-inhibitor complexes have been determined to atomic resolution. Analysis of these structures reveals that the main contributions to enzyme-inhibitor affinity can be approximated by a combination of dipole-induced dipole, dipole-quadrupole, and quadrupole-quadrupole interactions. Surprisingly, different electrostatic components dominate affinity in different enzyme-inhibitor pairs.