Structure-activity relationships of sulfonamide drugs and human carbonic anhydrase C: modeling of inhibitor molecules into the receptor site of the enzyme with an interactive computer graphics display.
Structure-activity relationships of sulfonamide drugs and human carbonic anhydrase C: modeling of inhibitor molecules into the receptor site of the enzyme with an interactive computer graphics display.
复制标题
磺酰胺药物和人碳酸酐酶 C 的结构-活性关系：通过交互式计算机图形显示将抑制剂分子建模到酶的受体位点。
DOI：
10.1002/jps.2600730316
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发表时间：
1984
影响因子：
3.8
通讯作者：
E. Meyer
中科院分区：
文献类型：
--
作者：
A. Vedani;E. Meyer
我们用交互式计算机图形显示技术分析了28种磺胺类抑制剂与人碳酸酐酶C（HCAC）的分子相互作用。小分子芳族磺酰胺类化合物对HCAC的抑制作用主要来自于酶的亲水性残基与帕拉或Meta位氢键受体的相互作用。额外的配位水分子稳定杂环磺酰胺的络合物（即，噻吩、1，3-噻唑和1，3，4-噻二唑）与HCAC的反应。我们提出了两种不同的模式结合的杂环相对于活性位点的裂缝：杂环硫原子的3，4-未取代的噻吩接近氧原子的配位水分子（硫“出”），而在3，4-未取代的1，3，4-噻二唑，硫是在接触的受体位点的疏水部分（硫“中”）。这一提议与晶体学证据相一致。具有两个芳环或杂环的磺酰胺也与位于距离活性位点金属Zn 2+大于10 A的酶的疏水口袋相互作用。我们还讨论了噻嗪类利尿剂的相对无活性是由于邻位氯原子与酶受体腔的空间相互作用造成的可能性。
We have analyzed the molecular interaction of 28 sulfonamide inhibitors with human carbonic anhydrase C (HCAC) using an interactive computer graphic display. Small aromatic sulfonamides gain most of their inhibitory power towards HCAC from the interaction of hydrogen bond acceptors at the para or meta positions with hydrophilic residues of the enzyme. Additional coordinated water molecules stabilize the complexes of heterocyclic sulfonamides (i.e., thiophenes, 1,3-thiazoles, and 1,3,4-thiadiazoles) with HCAC. We propose two different modes of binding of the heterocyclic ring with respect to the active site cleft: the heterocyclic sulfur atom of a 3,4-unsubstituted thiophene approaches the oxygen atom of a coordinated water molecule (sulfur "out"), whereas in 3,4-unsubstituted 1,3,4-thiadiazoles, the sulfur is in contact with a hydrophobic part of the receptor site (sulfur "in"). This proposal is consistent with crystallographic evidence. Sulfonamides with two aromatic or heterocyclic rings also interact with a hydrophobic pocket of the enzyme located greater than 10 A away from the active site metal Zn2+. We also discuss the possibility that the relative inactivity of thiazide diuretics is due to the steric interaction of the ortho chlorine atom with the enzyme receptor cavity.