研究硝基还原酶prodrug-activating系统。配合物的晶体结构抑制剂双香豆素和dinitrobenzamide高活性化合物和酶的活性形式。
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约翰逊E,帕金森GN,丹尼WA, Neidle年代
研究硝基还原酶prodrug-activating系统。配合物的晶体结构抑制剂双香豆素和dinitrobenzamide高活性化合物和酶的活性形式。
J地中海化学。2003年9月11日,46 (19):4009 - 20。
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12954054 (在PubMed]
- 文摘
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大肠杆菌硝基还原酶酶已广泛应用于的最惠国待遇自杀基因疗法(GDEPT和熟练的)应用程序作为硝基芳香化合物的活化酶的高活性dinitrobenzamide类。正常已被证明是一个关系homodimeric酶有两个活跃的网站。我们在座的简化型的晶体结构的正常与抑制剂双香豆素及其复合物和三个关系dinitrobenzamide高活性化合物。比较结构的氧化和减少形式的原生酶显示主要的结构性变化发生在单核苷酸FMN代数余子式和表明酶的本身是一种相对刚性结构,主要提供了一个刚性结构框架,氢化物发生转移。的aziridinyldinitrobenzamide前体药物CB 1954年不恒等的结合方式两个homodimeric酶的活性区域,采用疏水性和(active site B)直接接触H-bond Lys14的侧链。在活性位点FMN 2-nitro组栈之上,在活性位点B 4-nitro组,解释为什么还原硝基的观察。相比之下,更大的芥末组dinitrobenzamide芥末复合SN 23862部队的前体药物将在活动网站只有2-nitro集团能够参与FMN氢化物转移,解释为什么只有2-hydroxylamine减少产品。在每个站点,硝基的前体药物直接H-bond接触酶;在活性位点2-nitro Ser40和4-nitro Asn71,在活性位点B 2-nitro接触主链Thr41氮和4-nitro组Lys14侧链。相关amide-substituted芥末SN 27217将以类似的方式,但在更大的酰胺基的侧链取代基能够达到和联系Arg107,进一步限制了药物前体构象结合位点。 The inhibitor dicoumarol appears to bind primarily by pi-stacking interactions and hydrophobic contacts, with no conformational changes in the enzyme. One of the hydroxycoumarin subunits stacks above the plane of the FMN via pi-overlap with the isoalloxazine ring, penetrating deep into the groove, with the other less well-defined. These studies suggest guidelines for further prodrug design. Steric bulk (e.g., mustard rather than aziridine) on the ring can limit the possible binding orientations, and the reducible nitro group must be located para to the mustard. Substitution on the carboxamide side chain still allows the prodrugs to bind, but also limits their orientation in the binding site. Finally, modulating substrate specificity by alteration of the structure of the enzyme rather than the prodrug might usefully focus on modifying the Phe124 residue and those surrounding it.