title: In silico investigation of PARP-1 catalytic domains in holo and apo states for the design of high-affinity PARP-1 inhibitors.
abstract: The rational design of high-affinity inhibitors of poly-ADP-ribose polymerase-1 (PARP-1) is at the heart of modern anti-cancer drug design. While relevance of enzyme to DNA repair processes in cellular environment is firmly established, the structural and functional understanding of the main determinants for high-affinity ligands controlling PARP-1 activity is still lacking. The conserved active site of PARP-1 represents an ideal target for inhibitors and may offer a novel target at the treatment of breast cancer. To fill the gap in the structural knowledge, we report on the combination of molecular dynamics (MD) simulations, principal component analysis (PCA), and conformational analysis that analyzes in great details novel binding mode for a number of inhibitors at the PARP-1. While optimization of the binding affinity for original target is an important goal in the drug design, many of the promising molecules for treatment of the breast cancer are plagued by significant cardiotoxicity. One of the most common side-effects reported for a number of polymerase inhibitors is its off-target interactions with cardiac ion channels and hERG1 channel, in particular. Thus, selected candidate PARP-1 inhibitors were also screened in silico at the central cavities of hERG1 potassium ion channel.
authors.affiliation: a Department of Chemistry , Istanbul Technical University , Istanbul , Turkey .
authors.forename: Ramin Ekhteiari
authors.initials: RE
authors.lastname: Salmas
authors.affiliation: b Department of Biophysics , School of Medicine, Trakya University , Edirne , Turkey .
authors.forename: Ayhan
authors.initials: A
authors.lastname: Unlu
authors.affiliation: a Department of Chemistry , Istanbul Technical University , Istanbul , Turkey .
authors.forename: Mine
authors.initials: M
authors.lastname: Yurtsever
authors.affiliation: c Center for Molecular Simulation, Department of Biological Sciences, University of Calgary , Calgary , AB , Canada , and.
authors.forename: Sergei Y
authors.initials: SY
authors.lastname: Noskov
authors.affiliation: d Department of Biophysics , School of Medicine, Bahcesehir University , Istanbul , Turkey.
authors.forename: Serdar
authors.initials: S
authors.lastname: Durdagi
mesh_terms: D001051:Apoenzymes / Q000737:chemistry* / Q000378:metabolism; D055162:Biocatalysis; D020134:Catalytic Domain; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D020035:Holoenzymes / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001051:Apoenzymes; D020035:Holoenzymes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: MD simulations; PARP-1; molecular modeling