BASIS OF SELECTIVITY OF ANTIBACTERIAL DIAMINOPYRIMIDINES
BASIS OF SELECTIVITY OF ANTIBACTERIAL DIAMINOPYRIMIDINES
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DOI：
10.1080/1120009x.1993.11741086
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发表时间：
1993-12-01
影响因子：
1.8
通讯作者：
KUYPER, LF
中科院分区：
文献类型：
--
作者：
BACCANARI, DP;KUYPER, LF
综述了甲氧苄氨嘧啶[2，4-二氨基-5-（3 '，4'，5 '-三甲氧基苄基）嘧啶，TMP]及几种结构相近的类似物高亲和性和选择性的基础。2，4-二氨基苄基嘧啶苄基上的甲氧基取代显著影响大肠杆菌二氢叶酸还原酶（DHFR）的Ki值和体外抗菌活性。TMP比未取代的苄基嘧啶有效几百倍，并且单甲氧基和二甲氧基类似物具有中等活性。然而，在没有辅因子（NADPH）的情况下测定的平衡解离常数表明，这些二氨基苄基嘧啶在酶抑制剂二元复合物的结合是相当弱的，并没有在化合物之间变化。因此，E.在三元复合物中，NADPH增加了大肠杆菌DHFR的亲和力，这种增加的亲和力（协同性）随甲氧基取代而变化。相比之下，小鼠DHFR对二氨基苄基嘧啶的结合亲和力较弱，并且没有类似物显示出强烈的NADPH协同作用。细菌和哺乳动物DHFR之间NADPH/TMP协同性的大小差异是选择性的重要因素。急诊大肠杆菌酶在二元复合物中更强烈地结合TMP，并且由于协同性的差异而产生30倍的额外选择性因子。虽然细菌和脊椎动物DHFR的X射线晶体结构已经被广泛研究，没有一个单一的假设令人信服地解释TMP选择性的分子基础。然而，关于酶的三维结构的信息已被用于合理地设计新颖的、高亲和力的抑制剂。
The basis for the high affinity and selectivity of trimethoprim [2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine, TMP] and several close structural analogues is reviewed. Methoxy group substitution on the benzyl group of 2,4-diaminobenzylpyrimidine markedly affects both Escherichia coli dihydrofolate reductase (DHFR) K-i values and in vitro antibacterial activity. TMP is several hundred-fold more potent than the unsubstituted benzylpyrimidine, and the monomethoxy and dimethoxy analogues are of intermediate activity. However, equilibrium dissociation constants determined in the absence of cofactor (NADPH) show that the binding of these diaminobenzylpyrimidines in the enzyme-inhibitor binary complex is considerably weaker and does not vary among the compounds. Thus, the TMP binding affinity of E. coli DHFR is increased by NADPH in the ternary complex, and this increased affinity (cooperativity) varies with methoxy group substitution. In contrast, mouse DHFR has a weaker binding affinity for diaminobenzylpyrimidines, and none of the analogues show strong NADPH cooperative effects. The difference in the magnitude of NADPH/TMP cooperativity between bacterial and mammalian DHFR is an important factor in selectivity. The E. coli enzyme binds TMP more avidly in binary complex, and an additional selectivity factor of 30-fold arises from differences in cooperativity. Although the X-ray crystal structures of bacterial and vertebrate DHFR have been studied extensively, no single hypothesis convincingly explains the molecular basis of TMP selectivity. However, information on the three-dimensional structure of the enzyme has been used to rationally design novel, high-affinity inhibitors.