New Aryl Derivatives of Acridine with Poly (ADP- Ribose) Polymerase 1 Inhibitory Activity: A Molecular Modeling Approach

Sayantani Karmakar, Rita Ghosh

Abstract: Poly (ADP-ribose) polymerase 1 (PARP1) is a nuclear enzyme, involved in DNA repair and transcriptional regulation of genes that regulates cell survival and death. PARP1 inhibitors are therefore, often used with other drugs to enhance cell killing in cancer therapy. We present here our findings on the PARP1 inhibitory activities of some novel aryl acridines from molecular modelling studies. Like other established inhibitors of PARP1, these aryl acridines also bind to the nicotinamide adenine dinucleotide (NAD+) binding pocket of PARP1. They interact through non covalent ionic interactions and are capable of forming inter-molecular hydrogen bonds with several amino acids in this site, this includes all the important amino acid residues necessary for the catalytic activity of PARP1. The findings are important as this is the first report showing some acridine compounds as novel PARP1 inhibitors.

Keywords: PARP1, NAD+, 9 aryl acridines, Molecular Modeling, Molecular Docking