Design and experimental validation of small-molecule inhibitors of the FADD protein
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- 作者：N. V. Ivanisenko ; L. Hillert…
- 关键词：apoptosis ; CD95 ; FADD ; molecular modeling ; DISC ; caspase
- 刊名：Russian Journal of Genetics: Applied Research
- 出版年：2016
- 出版时间：November 2016
- 年：2016
- 卷：6
- 期：7
- 页码：778-784
- 全文大小：1,144 KB
- 刊物主题：Human Genetics;
- 出版者：Springer US
- ISSN：2079-0600
- 卷排序：6
文摘
CD95 is one of the best-studied members of the death receptor family. Activation of CD95 leads to the induction of the cell death program, apoptosis, via formation of the death-inducing signaling complex (DISC). The Fas-Associated Death Domain (FADD) is a key adaptor protein in the formation of the CD95 DISC and activation of procaspase 8 in the receptor complex. FADD comprises the death domain and the death effector domain (DED). The death domain is needed for the interactions of FADD with CD95, while DED is necessary for the recruitment of procaspases 8 and 10 and the cFLIP protein into the DISC. The search for specific inhibitors that would prevent the interactions of FADD with other core proteins of the DISC is important for the studies of the structure and function of this complex, investigation of apoptosis mechanisms, and development of new treatments for neurodegenerative diseases. In the course of this work, an in silico screening for low-molecular-weight inhibitors that would selectively interact with FADD DED was performed. This work required the molecular modeling of the protein complexes and virtual screening of potential FADD inhibitors. In addition, a new technology to test the activity of these inhibitors was developed. The computational and experimental analysis allowed us to characterize the optimum conformation of FADD for the design of small molecules that would bind to the region of the amino acid residue F25. We presume that further optimization of the structures of the chemical compounds that can bind within the hydrophobic pocket next to F25 of FADD will allow the development of new candidate inhibitors of programmed cell death.