International Journal of Science and Research (IJSR) ISSN (Online): 2319-7064 Index Copernicus Value (2013): 6.14 | Impact Factor (2014): 5.611 Volume 4 Issue 12, December 2015 www.ijsr.net Licensed Under Creative Commons Attribution CC BY New Aryl Derivatives of Acridine with Poly (ADP- Ribose) Polymerase 1 Inhibitory Activity: A Molecular Modeling Approach Sayantani Karmakar 1 , Rita Ghosh 2* 1, 2 Department of Biochemistry and Biophysics, University of Kalyani, Kalyani-741235, West Bengal, India 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 1. Introduction 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 [1]. PARP1 response is provoked by genotoxic stress on DNA. It senses breaks in DNA and catalyses the addition of ADP- ribose onto different nucleosomal proteins and also onto itself, as linear or branched PAR chains using NAD + as its substrate [2]. The poly (ADP-ribosyl)ation of the histone proteins helps to draw away the nucleosomal proteins from DNA to facilitate DNA repair [3]. Inhibition of PARP1 activity thus sensitizes cells to killing by different damaging agents [4, 5]. PARP1 inhibitors are therefore important in cancer chemotherapeutics [6]. The primary structure of PARP1 consists of 1014 residues organized in 3 functionally distinct domains: i) DNA binding N terminal domain, ii) auto-modification domain for ADP ribosylation and iii) catalytic domain at the C terminal region [7]. The catalytic site consists of residues 654 to 1014 and includes importantly the residues Tyr710, Gln763, Asp766, Asn767, Asp770, Trp861, His862, Gly863, Ser864, Arg878, Ile879, Ala880, Gly888, Tyr889, Met890, Gly894, Tyr896, Phe897, Ala898, Lys903, Ser904, Tyr907, Asn987, Glu988 and Tyr989 [8]. Ruf et al. predicted that the putative NAD + binding site resides in the catalytic region [9]. Within the catalytic site, the NAD + binding pocket is lined by the residues His862, Gly863, Tyr896, Phe897, Ala898, Lys903, Ser904, Tyr907 and Glu988 [10]. Different PARP1 inhibitors bind at the NAD + binding pocket to exert their inhibitory effect [10]. Acridine derivatives are known to interact with different key enzymes [11, 12] to exhibit antitumor activity [13-15]. Particularly important are the derivatives at C 9 position [16, 17].The biological activities of phenyl-derivatives at C 9 position were so far less explored. From our earlier works the biological importance of some aryl derivatives of acridine are already documented [18, 19] and the antitumor action have been demonstrated in different cancer cell lines as well as in animal model [20]. Aryl acridine derivatives can also potentiate cell killing by other agents (our unpublished results). We therefore wanted to explore whether any of these derivatives can have PARP1 inhibitory activity. We present here the molecular modeling studies on interaction of some 9 aryl acridine derivatives with chicken PARP1. Human PARP1 is a homo-dimer that shares strong sequence similarity with chicken PARP1 (87%). The amino acid residues around the active site of PARP1 from both the species are perfectly conserved [21]. The monomeric chicken PARP1 is most often used for studying the inhibitory potentials of different drugs [8-10]. Human and chicken numbering of amino acids differs by three [9]; since human PARP1 is the drug target, the human numbering is used conventionally in all reports. Our preliminary findings indicate that these acridines are likely to exert inhibitory effect on PARP1 by blocking the binding of NAD + at the catalytic region of PARP1. 2. Materials and methods 2.1 Generation of three dimensional structures of ligands The three dimensional coordinates of 9 aryl derivatives of acridine were generated and optimized in three dimensional space using the program ACD/ChemSketch (http://www.acdlabs.com/download/chemsk.html) and PyMOL 7.2 [22]. The programs generate the backbone coordinates of the molecules first and then add the side chain atoms. In order to relieve the steric strain in the molecule, the entire molecule was energy minimized. The energy minimization was done using the Conjugate Gradient (CG) algorithm with CHARMm force-fields until the structures reached the final energy derivative of 0.001 kcal / mole. A total of 500 steps of energy minimizations were performed for the 9 aryl derivatives of acridine. The final energy minimized structures of the 9 aryl derivatives of acridine were used for further docking analysis. The coordinates of Paper ID: NOV152257 1362