Structure-Based Design of Anticancer Prodrug PABA/NO.
Structure-Based Design of Anticancer Prodrug PABA/NO.
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DOI：
10.2147/dddt.s3931
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Singh SV
中科院分区：
文献类型：
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作者：
Ji X;Pal A;Kalathur R;Hu X;Gu Y;Saavedra JE;Buzard GS;Srinivasan A;Keefer LK;Singh SV
谷胱甘肽S-转移酶（GST）是一个解毒酶超家族，以GSTα、GSTμ、GSTπ等为代表，GSTα是人体肝脏中GST的主要异构体，对人体健康起着重要作用。GSTπ在许多形式的癌症中过表达，因此提供了选择性靶向癌细胞的机会。我们基于结构设计的前药旨在释放GSTπ过表达癌细胞中的细胞毒性水平的一氧化氮，产生PABA/NO，其在体外和体内均表现出抗癌活性，其效力与顺铂相似。在这里，我们提出了详细的结构修饰，分子建模，和酶的特性的设计PABA/NO。设计是有效的，因为它是在反应机理和结构的基础上相关的GST同工酶在基态和过渡态。基态结构描述了不同同工酶底物结合位点的形状和性质，过渡态结构信息显示了不同同工酶活性位点上前药Meisenheimer复合物的不同构象，为前药分子结构的修饰提供了指导。GSTα-选择性化合物的两个关键改变导致GSTπ-选择性PABA/NO。
Glutathione S-transferase (GST) is a superfamily of detoxification enzymes, represented by GSTα, GSTμ, GSTπ, etc. GSTα is the predominant isoform of GST in human liver, playing important roles for our well being. GSTπ is overexpressed in many forms of cancer, thus presenting an opportunity for selective targeting of cancer cells. Our structure-based design of prodrugs intended to release cytotoxic levels of nitric oxide in GSTπ-overexpressing cancer cells yielded PABA/NO, which exhibited anticancer activity both in vitro and in vivo with a potency similar to that of cisplatin. Here, we present the details on structural modification, molecular modeling, and enzymatic characterization for the design of PABA/NO. The design was efficient because it was on the basis of the reaction mechanism and the structures of related GST isozymes at both the ground state and the transition state. The ground-state structures outlined the shape and property of the substrate-binding site in different isozymes, and the structural information at the transition-state indicated distinct conformations of the Meisenheimer complex of prodrugs in the active site of different isozymes, providing guidance for the modifications of the molecular structure of the prodrug molecules. Two key alterations of a GSTα-selective compound led to the GSTπ-selective PABA/NO.