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2,5-Diketopiperazines: A New Class of Poly(ADP-ribose)polymerase Inhibitors

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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.

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Abbreviations

PARP:

poly(ADP-ribose)polymerase.

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Authors and Affiliations

  1. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    D. K. Nilov & V. K. Švedas

  2. Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991, Moscow, Russia

    K. I. Yashina, I. V. Gushchina & V. K. Švedas

  3. Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090, Novosibirsk, Russia

    A. L. Zakharenko, M. V. Sukhanova & O. I. Lavrik

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  1. D. K. Nilov
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  2. K. I. Yashina
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  3. I. V. Gushchina
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Correspondence to V. K. Švedas.

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Published in Russian in Biokhimiya, 2018, Vol. 83, No. 2, pp. 251-258.

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Nilov, D.K., Yashina, K.I., Gushchina, I.V. et al. 2,5-Diketopiperazines: A New Class of Poly(ADP-ribose)polymerase Inhibitors. Biochemistry Moscow 83, 152–158 (2018). https://doi.org/10.1134/S0006297918020074

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