2,5-Diketopiperazines: A New Class of Poly(ADP-ribose)polymerase Inhibitors
- Authors: Nilov D.K.1, Yashina K.I.2, Gushchina I.V.2, Zakharenko A.L.3, Sukhanova M.V.3, Lavrik O.I.3, Švedas V.K.1,2
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Affiliations:
- Belozersky Institute of Physico-Chemical Biology
- Faculty of Bioengineering and Bioinformatics
- Institute of Chemical Biology and Fundamental Medicine
- Issue: Vol 83, No 2 (2018)
- Pages: 152-158
- Section: Article
- URL: https://journals.rcsi.science/0006-2979/article/view/151601
- DOI: https://doi.org/10.1134/S0006297918020074
- ID: 151601
Cite item
Abstract
We show for the first time that natural 2,5-diketopiperazines (cyclic dipeptides) can suppress the activity of the important anticancer target poly(ADP-ribose)polymerase (PARP). Cyclo(L-Ala-L-Ala) and cyclo(L-Ala-D-Ala) can interact with the key residues of the PARP-1 active site, as demonstrated using docking and molecular dynamics simulations. One of the amide groups of cyclo(L-Ala-L-Ala) and cyclo(L-Ala-D-Ala) forms hydrogen bonds with the Gly863 residue, while the second amide group can form a hydrogen bond with the catalytic residue Glu988, and the side chain can make a hydrophobic contact with Ala898. Newly identified diketopiperazine inhibitors are promising basic structures for the design of more effective inhibitors of PARP family enzymes. The piperazine core with two chiral centers provides many opportunities for structural optimization.
About the authors
D. K. Nilov
Belozersky Institute of Physico-Chemical Biology
Email: vytas@belozersky.msu.ru
Russian Federation, Moscow, 119991
K. I. Yashina
Faculty of Bioengineering and Bioinformatics
Email: vytas@belozersky.msu.ru
Russian Federation, Moscow, 119991
I. V. Gushchina
Faculty of Bioengineering and Bioinformatics
Email: vytas@belozersky.msu.ru
Russian Federation, Moscow, 119991
A. L. Zakharenko
Institute of Chemical Biology and Fundamental Medicine
Email: vytas@belozersky.msu.ru
Russian Federation, Novosibirsk, 630090
M. V. Sukhanova
Institute of Chemical Biology and Fundamental Medicine
Email: vytas@belozersky.msu.ru
Russian Federation, Novosibirsk, 630090
O. I. Lavrik
Institute of Chemical Biology and Fundamental Medicine
Email: vytas@belozersky.msu.ru
Russian Federation, Novosibirsk, 630090
V. K. Švedas
Belozersky Institute of Physico-Chemical Biology; Faculty of Bioengineering and Bioinformatics
Author for correspondence.
Email: vytas@belozersky.msu.ru
Russian Federation, Moscow, 119991; Moscow, 119991