Abstract
The nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) plays an important role in the signaling and repair of DNA. PARP-1 catalyses the covalent binding of poly (ADP-ribose) polymers to its subunit, as well as to other acceptor proteins, using NAD+ as a donor of ADP-ribose. Inhibitors of poly (ADP-ribose) polymerase have been shown to be effective in improving radiation therapy and chemotherapy of cancer in clinical testing. Development of new poly (ADP-ribose) polymerase-1 inhibitors based on derivatives of natural compounds such as NAD+ represents a novel and promising strategy. The structure of the complex of human poly (ADP-ribose) polymerase-1 with NAD+ can be a starting point for the rational design of small molecule inhibitors based on NAD+ derivatives. Moreover, there is no crystal structure of the complex of poly (ADP-ribose) polymerase-1 with nicotinamide adenine dinucleotide (NAD+) available yet. In this work, using molecular modeling approaches, we have predicted NAD+ binding modes to PARP-1 at the donor binding site of the catalytic domain. Using structures of PARP-1 homologs in a complex with NAD+, we predict the pharmacophore restraints of NAD+ binding to PARP-1. Based on the clustering of PARP-1 conformations in a complex with cocrystallized inhibitors and the predicted pharmacophore restraints, we propose several possible models of NAD+ binding to PARP-1 at the donor binding site of the catalytic domain. According to the predicted models, two conformations for the pyrophosphate group of NAD+ in complex with PARP-1 at the donor binding site are possible. The proposed models of NAD+ binding to PARP-1 can be validated by the quantitative structure–activity analysis of NAD+ derivatives. We designed two NAD+ derivatives, which can be used to validate the predicted NAD+ binding models.
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Original Russian Text © N.V. Ivanisenko, D.A. Zhechev, V.A. Ivanisenko, 2016, published in Vavilovskii Zhurnal Genetiki i Selektsii, 2016, Vol. 20, No. 6, pp. 857–862.
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Ivanisenko, N.V., Zhechev, D.A. & Ivanisenko, V.A. Structural modeling of NAD+ binding modes to PARP-1. Russ J Genet Appl Res 7, 574–579 (2017). https://doi.org/10.1134/S2079059717050070
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DOI: https://doi.org/10.1134/S2079059717050070