Inhibition of Poly(ADP-Ribose) Polymerase by Nucleic Acid Metabolite 7-Methylguanine

D K Nilov; V I Tararov; A V Kulikov; A L Zakharenko; I V Gushchina; S N Mikhailov; O I Lavrik; V K Švedas

Inhibition of Poly(ADP-Ribose) Polymerase by Nucleic Acid Metabolite 7-Methylguanine

Acta Naturae. 2016 Apr-Jun;8(2):108-15.

Authors

D K Nilov¹, V I Tararov², A V Kulikov³, A L Zakharenko⁴, I V Gushchina⁵, S N Mikhailov², O I Lavrik⁴, V K Švedas¹

Affiliations

¹ Lomonosov Moscow State University, Belozersky Institute of Physicochemical Biology, Leninskie Gory 1, bldg. 40, Moscow, 119991, Russia ; Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Leninskie Gory 1, bldg. 73, Moscow, 119991, Russia.
² Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov str. 32, Moscow, 119991 , Russia.
³ Lomonosov Moscow State University, Faculty of Fundamental Medicine, Lomonosovsky avenue 31 -5, Moscow, 119192, Russia.
⁴ Institute of Chemical Biology and Fundamental Medicine, Russian Academy of Sciences, Siberian Branch, Lavrentiev avenue 8, Novosibirsk, 630090, Russia.
⁵ Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, Leninskie Gory 1, bldg. 73, Moscow, 119991, Russia.

PMID: 27437145
PMCID: PMC4947994

Abstract

The ability of 7-methylguanine, a nucleic acid metabolite, to inhibit poly(ADP-ribose)polymerase-1 (PARP-1) and poly(ADP-ribose)polymerase-2 (PARP-2) has been identified in silico and studied experimentally. The amino group at position 2 and the methyl group at position 7 were shown to be important substituents for the efficient binding of purine derivatives to PARPs. The activity of both tested enzymes, PARP-1 and PARP-2, was suppressed by 7-methylguanine with IC50 values of 150 and 50 μM, respectively. At the PARP inhibitory concentration, 7-methylguanine itself was not cytotoxic, but it was able to accelerate apoptotic death of BRCA1-deficient breast cancer cells induced by cisplatin and doxorubicin, the widely used DNA-damaging chemotherapeutic agents. 7-Methylguanine possesses attractive predictable pharmacokinetics and an adverse-effect profile and may be considered as a new additive to chemotherapeutic treatment.

Keywords: PARP inhibitors; docking; molecular modeling.