Multimeric naphthoquinones are redox-active compounds that exhibit antineoplastic, antiprotozoal, and antiviral activities. Due to their multimodal effect on perturbation of cellular oxidative state, these compounds hold great potential as therapeutic agents against highly proliferative neoplastic cells.
In our previous work, we developed a series of novel dimeric naphthoquinones and showed that they were selectively cytotoxic to human acute myeloid leukemia (AML), breast and prostate cancer cell lines. We subsequently identified the oxidoreductase NAD(P)H dehydrogenase, quinone 1 (NQO1) as the major target of dimeric naphthoquinones and proposed a mechanism of action that entailed induction of a futile redox cycling.
Here, for the first time, we describe a direct physical interaction between the bromohydroxy dimeric naphthoquinone E6a and NQO1. Moreover, our studies reveal an extensive binding interface between E6a and the isoalloxazine ring of the flavin adenine dinucleotide (FAD) cofactor of NQO1 in addition to interactions with protein side chains in the active site. We also present biochemical evidence that dimeric naphthoquinones affect the redox state of the FAD cofactor of NQO1. Comparison of the mode of binding of E6a with those of other chemotherapeutics reveals unique characteristics of the interaction that can be leveraged in future drug optimization efforts.
The first structure of a dimeric naphthoquinone-NQO1 complex was reported, which can be used for design and synthesis of more potent next generation dimeric naphthoquinones to target NQO1 with higher affinity and specificity.
BMC structural biology. 2016 Jan 28*** epublish ***
Lakshmi Swarna Mukhi Pidugu, J C Emmanuel Mbimba, Muqeet Ahmad, Edwin Pozharski, Edward A Sausville, Ashkan Emadi, Eric A Toth
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. Institute for Bioscience and Biotechnology Research, and Center for Biomolecular Therapeutics, 9600 Gudelsky Drive, Rockville, MD, 20850, USA. Institute for Bioscience and Biotechnology Research, and Center for Biomolecular Therapeutics, 9600 Gudelsky Drive, Rockville, MD, 20850, USA. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.