Structure-based design of anticancer prodrug PABA/NO
Xinhua Ji1, Ajai Pal2, Ravi Kalathur1, Xun Hu2, Yijun Gu1,2, Joseph E Saavedra3, Gregory S Buzard3, Aloka Srinivasan4, Larry K Keefer4, Shivendra V Singh2
1Macromolecular Crystallography Laboratory, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; 2Department of Pharmacology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; 3Basic Research Program, SAIC-Frederick Inc., Frederick, MD 21702, USA; 4Laboratory of Comparative Carcinogenesis, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
Abstract: 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.
Keywords: structure-based, drug design, anticancer, prodrug, PABA/NO
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