Structural modeling of NAD+ binding modes to PARP-1
The nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) plays an important role in the signaling and repair of DNA. PARP-1 catalyses covalent binding of poly (ADP-ribose) polymers with itself as well as with other acceptor proteins using NAD+ as a donor of ADP-ribose. Inhibitors of poly (ADP-rib...
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Siberian Branch of the Russian Academy of Sciences, Federal Research Center Institute of Cytology and Genetics, The Vavilov Society of Geneticists and Breeders
2017-02-01
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| Series: | Вавиловский журнал генетики и селекции |
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| Online Access: | https://vavilov.elpub.ru/jour/article/view/861 |
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| author | N. V. Ivanisenko D. A. Zhechev V. A. Ivanisenko |
| author_facet | N. V. Ivanisenko D. A. Zhechev V. A. Ivanisenko |
| author_sort | N. V. Ivanisenko |
| collection | DOAJ |
| description | The nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) plays an important role in the signaling and repair of DNA. PARP-1 catalyses covalent binding of poly (ADP-ribose) polymers with itself as well as with other acceptor proteins using NAD+ as a donor of ADP-ribose. Inhibitors of poly (ADP-ribose) polymerase have been shown to be effective in improvement of 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 complex of human poly (ADP-ribose) polymerase-1 with NAD+ can be a starting point for rational design of small molecule inhibitors based on NAD+ derivatives. Indeed there is no crystal structure of complex 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 with PARP-1 at the donor binding site of the catalytic domain. Using structures of PARP-1 homologs in complex with NAD+ we predicted pharmacophore restraints of NAD+ binding to PARP-1. Based on clustering of PARP-1 conformations in complex with co-crystallized inhibitors and predicted pharmacophore restraints, we proposed 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 of pyrophosphate group of NAD+ in complex with PARP-1 at the donor binding site are possible. Validation of the proposed models of NAD+ binding with PARP-1 can be achieved by quantitative structure-activity analysis of NAD+ derivatives. We designed two NAD+ derivatives, which can be used for validation of predicted NAD+ binding models. |
| format | Article |
| id | doaj-art-6b31dce709bd43c4be825f9fabc1e6cf |
| institution | Kabale University |
| issn | 2500-3259 |
| language | English |
| publishDate | 2017-02-01 |
| publisher | Siberian Branch of the Russian Academy of Sciences, Federal Research Center Institute of Cytology and Genetics, The Vavilov Society of Geneticists and Breeders |
| record_format | Article |
| series | Вавиловский журнал генетики и селекции |
| spelling | doaj-art-6b31dce709bd43c4be825f9fabc1e6cf2025-02-01T09:58:03ZengSiberian Branch of the Russian Academy of Sciences, Federal Research Center Institute of Cytology and Genetics, The Vavilov Society of Geneticists and BreedersВавиловский журнал генетики и селекции2500-32592017-02-0120685786210.18699/VJ16.202550Structural modeling of NAD+ binding modes to PARP-1N. V. Ivanisenko0D. A. Zhechev1V. A. Ivanisenko2Institute of Cytology and Genetics SB RAS Novosibirsk State UniversityInstitute of Cytology and Genetics SB RASInstitute of Cytology and Genetics SB RASThe nuclear protein poly (ADP-ribose) polymerase-1 (PARP-1) plays an important role in the signaling and repair of DNA. PARP-1 catalyses covalent binding of poly (ADP-ribose) polymers with itself as well as with other acceptor proteins using NAD+ as a donor of ADP-ribose. Inhibitors of poly (ADP-ribose) polymerase have been shown to be effective in improvement of 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 complex of human poly (ADP-ribose) polymerase-1 with NAD+ can be a starting point for rational design of small molecule inhibitors based on NAD+ derivatives. Indeed there is no crystal structure of complex 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 with PARP-1 at the donor binding site of the catalytic domain. Using structures of PARP-1 homologs in complex with NAD+ we predicted pharmacophore restraints of NAD+ binding to PARP-1. Based on clustering of PARP-1 conformations in complex with co-crystallized inhibitors and predicted pharmacophore restraints, we proposed 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 of pyrophosphate group of NAD+ in complex with PARP-1 at the donor binding site are possible. Validation of the proposed models of NAD+ binding with PARP-1 can be achieved by quantitative structure-activity analysis of NAD+ derivatives. We designed two NAD+ derivatives, which can be used for validation of predicted NAD+ binding models.https://vavilov.elpub.ru/jour/article/view/861parp-1nad+structural model |
| spellingShingle | N. V. Ivanisenko D. A. Zhechev V. A. Ivanisenko Structural modeling of NAD+ binding modes to PARP-1 Вавиловский журнал генетики и селекции parp-1 nad+ structural model |
| title | Structural modeling of NAD+ binding modes to PARP-1 |
| title_full | Structural modeling of NAD+ binding modes to PARP-1 |
| title_fullStr | Structural modeling of NAD+ binding modes to PARP-1 |
| title_full_unstemmed | Structural modeling of NAD+ binding modes to PARP-1 |
| title_short | Structural modeling of NAD+ binding modes to PARP-1 |
| title_sort | structural modeling of nad binding modes to parp 1 |
| topic | parp-1 nad+ structural model |
| url | https://vavilov.elpub.ru/jour/article/view/861 |
| work_keys_str_mv | AT nvivanisenko structuralmodelingofnadbindingmodestoparp1 AT dazhechev structuralmodelingofnadbindingmodestoparp1 AT vaivanisenko structuralmodelingofnadbindingmodestoparp1 |