*Article* **Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine**

**Dmitry Nilov 1,\* , Natalya Maluchenko <sup>2</sup> , Tatyana Kurgina 3,4, Sergey Pushkarev <sup>5</sup> , Alexandra Lys <sup>2</sup> , Mikhail Kutuzov <sup>3</sup> , Nadezhda Gerasimova <sup>2</sup> , Alexey Feofanov 2,6 , Vytas Švedas 1,5 , Olga Lavrik 3,4 and Vasily M. Studitsky 2,7,\***


Received: 28 January 2020; Accepted: 17 March 2020; Published: 20 March 2020

**Abstract:** 7-Methylguanine (7-MG), a natural compound that inhibits DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1), can be considered as a potential anticancer drug candidate. Here we describe a study of 7-MG inhibition mechanism using molecular dynamics, fluorescence anisotropy and single-particle Förster resonance energy transfer (spFRET) microscopy approaches to elucidate intermolecular interactions between 7-MG, PARP-1 and nucleosomal DNA. It is shown that 7-MG competes with substrate NAD<sup>+</sup> and its binding in the PARP-1 active site is mediated by hydrogen bonds and nonpolar interactions with the Gly863, Ala898, Ser904, and Tyr907 residues. 7-MG promotes formation of the PARP-1–nucleosome complexes and suppresses DNA-dependent PARP-1 automodification. This results in nonproductive trapping of PARP-1 on nucleosomes and likely prevents the removal of genotoxic DNA lesions.

**Keywords:** 7-methylguanine; poly(ADP-ribose) polymerase 1; inhibitor; nucleosome; trapping; docking; molecular dynamics; fluorescence anisotropy; spFRET microscopy
