INCREASING BINDING CONSTANTS OF LIGANDS TO CARBONIC-ANHYDRASE BY USING GREASY TAILS
INCREASING BINDING CONSTANTS OF LIGANDS TO CARBONIC-ANHYDRASE BY USING GREASY TAILS
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DOI：
10.1021/jm00013a005
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发表时间：
1995-06-23
影响因子：
7.3
通讯作者：
WHITESIDES, GM
中科院分区：
文献类型：
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作者：
GAO, JM;QIAO, S;WHITESIDES, GM
已经检测了两个系列的对位取代的苯磺酰胺作为牛碳酸酐酶II（CAII，EC 4.2.1.1）的抑制剂。两个系列都具有通过酰胺键连接到芳环的疏水烷基R（H2 NO2 SC 6 H4-CH（2）NHCOR（1）和H2 NO2 SC 6 H4-CONR（2）R（3））。这些配体在水和辛醇之间的分配自由能（Δ Gp）与疏水基团R的分子表面积具有类似的线性相关性; Δ Gp仅受苯磺酰胺的连接和基团R的详细结构的相对较弱的影响。这些配体与CAII的结合更为复杂。对于具有结构H2 NO2 SC 6 H4-L-R的化合物，对于不同的-L-R，与CAII结合的自由能对烃（碳氟化合物）基团R的表面积的依赖性为（d Δ G（B）/dA，kcal/（mol . -CH（2）NHCOR（H），-0.71 +/-0.03; -CH（2）NHCOR（F），-0.72 +/-0.07; -CONHCH（2）R（H），-2.5 +/-0.1;和-CONHCH（2）R（F），-2.7 +/-0.3。现有数据允许几个结论：（一）细节基团R（H）的结构的（直链的、支链的、环状的）性质在确定结合常数方面相对不重要（尽管环状结构可以比具有相同碳数的非环状配体稍微更强地结合）;（ii）对于给定类别的化合物，具有相同表面积的烃和碳氟化合物的结合常数非常相似;和（iii）接头L的性质影响与基团R的表面积结合的灵敏度，推测是通过其在酶的结合口袋中定位基团的影响。碳氟化合物似乎比相同碳数的碳氢化合物更疏水，因为它们具有更大的疏水表面面积;碳氢化合物和碳氟化合物表面的疏水性在校正面积差异后相似。
Two series of para-substituted benzenesulfonamides have been examined as inhibitors for bovine carbonic anhydrase II (CAII, EC 4.2.1.1). Both series have hydrophobic alkyl group R connected by amide linkages to the aromatic ring (H2NO2SC6H4-CH(2)NHCOR(1) and H2NO2SC6H4-CONR(2)R(3)). The free energy of partitioning (Delta Gp) Of these ligands between water and octanol had similar, linear correlations with the molecular surface areas of the hydrophobic groups R; Delta Gp was only relatively weakly influenced by the Linkage to the benzenesulfonamide and the detailed structure of the group R. Binding of these ligands to CAII was more complicated. For compounds having the structure H2NO2SC6H4-L-R, the dependence of the free energy of binding to CAII on the surface area of the hydrocarbon (fluorocarbon) group R for different -L-R was (d Delta G(b)/dA, kcal/(mol . 100 Angstrom(2))): -CH(2)NHCOR(H), -0.71 +/- 0.03; -CH(2)NHCOR(F), -0.72 +/- 0.07; -CONHCH(2)R(H), -2.5 +/- 0.1; and -CONHCH(2)R(F), -2.7 +/- 0.3. The available data permit several conclusions: (i) details (linear, branched, cyclic) of the structure of the group R(H) are relatively unimportant in determining binding constants (although cyclic structures may bind slightly more strongly than acyclic ligands with the same carbon number); (ii) for a given class of compounds, binding constants of hydrocarbons and fluorocarbons having the same surface area are very similar; and (iii) the nature of the linker L influences the sensitivity of binding to the surface area of the group R, presumably by its influences in positioning the group in the binding pocket of the enzyme. Fluorocarbons seem to be more hydrophobic than hydrocarbons of the same carbon number because they have larger areas of hydrophobic surface; the hydrophobicity of hydrocarbon and fluorocarbon surfaces are similar, after correction for differences in area.