Design and experimental validation of the action of small molecule-based inhibitors of the FADD protein
CD95 is one of the best studied members of the death receptor family. Activation of CD95 leads to the induction of the cell death programme, apoptosis, via formation of the death-inducing signaling complex (DISC). FA DD is a key adaptor protein for the formation of the C D95 DISC and activation of c...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Siberian Branch of the Russian Academy of Sciences, Federal Research Center Institute of Cytology and Genetics, The Vavilov Society of Geneticists and Breeders
2016-01-01
|
| Series: | Вавиловский журнал генетики и селекции |
| Subjects: | |
| Online Access: | https://vavilov.elpub.ru/jour/article/view/490 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832575229396779008 |
|---|---|
| author | N. V. Ivanisenko L. Hillert V. A. Ivanisenko I. N. Lavrik |
| author_facet | N. V. Ivanisenko L. Hillert V. A. Ivanisenko I. N. Lavrik |
| author_sort | N. V. Ivanisenko |
| collection | DOAJ |
| description | CD95 is one of the best studied members of the death receptor family. Activation of CD95 leads to the induction of the cell death programme, apoptosis, via formation of the death-inducing signaling complex (DISC). FA DD is a key adaptor protein for the formation of the C D95 DISC and activation of caspase-8 in the receptor complex. FA DD comprises the death domain and the death effector domain (DED). The death domain is essential for the interactions of FA DD with CD95, while DED is necessary for the recruitment of procaspase-8, -10 and the protein c-FLIP into the DISC. The search for the inhibitors that would block the interactions of FA DD with the other core proteins of the DISC is essential for the studies of the structure and function of this complex, investigation of the apoptosis mechanisms and development of new treatments for neurodegenerative diseases. In the course of this work, the screening for small inhibitors in silico that selectively interact with DED has been performed. For this purpose, the molecular modeling of the protein complexes and virtual screening of the potential inhibitors of FA DD has been performed. In addition, a new technology to test the activity of these inhibitors has been developed. The computational and experimental analysis performed allowed us to characterize the optimal conformation of the FA DD protein for the design of the small molecules that can bind in the region of amino acid residue Y25. We presume that further optimization of the structures of chemical compounds that can bind with the hydrophobic pocket next to the residue Y25 of FA DD will allow for the creation of the new perspective inhibitors of the programmed cell death. |
| format | Article |
| id | doaj-art-617bf55894fa4817a82964fa1ba3a570 |
| institution | Kabale University |
| issn | 2500-3259 |
| language | English |
| publishDate | 2016-01-01 |
| 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-617bf55894fa4817a82964fa1ba3a5702025-02-01T09:58:02ZengSiberian 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 селекции2500-32592016-01-0119672473010.18699/VJ15.084433Design and experimental validation of the action of small molecule-based inhibitors of the FADD proteinN. V. Ivanisenko0L. Hillert1V. A. Ivanisenko2I. N. Lavrik3Institute of Cytology and Genetics SB RA S, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, RussiaDepartment of Translational Inflammation, Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, GermanyInstitute of Cytology and Genetics SB RA S, Novosibirsk, RussiaInstitute of Cytology and Genetics SB RA S, Novosibirsk, Russia Department of Translational Inflammation, Institute of Experimental Internal Medicine, Otto von Guericke University, Magdeburg, GermanyCD95 is one of the best studied members of the death receptor family. Activation of CD95 leads to the induction of the cell death programme, apoptosis, via formation of the death-inducing signaling complex (DISC). FA DD is a key adaptor protein for the formation of the C D95 DISC and activation of caspase-8 in the receptor complex. FA DD comprises the death domain and the death effector domain (DED). The death domain is essential for the interactions of FA DD with CD95, while DED is necessary for the recruitment of procaspase-8, -10 and the protein c-FLIP into the DISC. The search for the inhibitors that would block the interactions of FA DD with the other core proteins of the DISC is essential for the studies of the structure and function of this complex, investigation of the apoptosis mechanisms and development of new treatments for neurodegenerative diseases. In the course of this work, the screening for small inhibitors in silico that selectively interact with DED has been performed. For this purpose, the molecular modeling of the protein complexes and virtual screening of the potential inhibitors of FA DD has been performed. In addition, a new technology to test the activity of these inhibitors has been developed. The computational and experimental analysis performed allowed us to characterize the optimal conformation of the FA DD protein for the design of the small molecules that can bind in the region of amino acid residue Y25. We presume that further optimization of the structures of chemical compounds that can bind with the hydrophobic pocket next to the residue Y25 of FA DD will allow for the creation of the new perspective inhibitors of the programmed cell death.https://vavilov.elpub.ru/jour/article/view/490apoptosiscd95fa ddmolecular modelingdisccaspase |
| spellingShingle | N. V. Ivanisenko L. Hillert V. A. Ivanisenko I. N. Lavrik Design and experimental validation of the action of small molecule-based inhibitors of the FADD protein Вавиловский журнал генетики и селекции apoptosis cd95 fa dd molecular modeling disc caspase |
| title | Design and experimental validation of the action of small molecule-based inhibitors of the FADD protein |
| title_full | Design and experimental validation of the action of small molecule-based inhibitors of the FADD protein |
| title_fullStr | Design and experimental validation of the action of small molecule-based inhibitors of the FADD protein |
| title_full_unstemmed | Design and experimental validation of the action of small molecule-based inhibitors of the FADD protein |
| title_short | Design and experimental validation of the action of small molecule-based inhibitors of the FADD protein |
| title_sort | design and experimental validation of the action of small molecule based inhibitors of the fadd protein |
| topic | apoptosis cd95 fa dd molecular modeling disc caspase |
| url | https://vavilov.elpub.ru/jour/article/view/490 |
| work_keys_str_mv | AT nvivanisenko designandexperimentalvalidationoftheactionofsmallmoleculebasedinhibitorsofthefaddprotein AT lhillert designandexperimentalvalidationoftheactionofsmallmoleculebasedinhibitorsofthefaddprotein AT vaivanisenko designandexperimentalvalidationoftheactionofsmallmoleculebasedinhibitorsofthefaddprotein AT inlavrik designandexperimentalvalidationoftheactionofsmallmoleculebasedinhibitorsofthefaddprotein |