title: In Silico Screening Identifies a Novel Potential PARP1 Inhibitor Targeting Synthetic Lethality in Cancer Treatment.
abstract: Synthetic lethality describes situations in which defects in two different genes or pathways together result in cell death. This concept has been applied to drug development for cancer treatment, as represented by Poly (ADP-ribose) polymerase (PARPs) inhibitors. In the current study, we performed a computational screening to discover new PARP inhibitors. Among the 11,247 compounds analyzed, one natural product, ZINC67913374, stood out by its superior performance in the simulation analyses. Compared with the FDA approved PARP1 inhibitor, olaparib, our results demonstrated that the ZINC67913374 compound achieved a better grid score (-86.8) and amber score (-51.42). Molecular dynamics simulations suggested that the PARP1-ZINC67913374 complex was more stable than olaparib. The binding free energy for ZINC67913374 was -177.28 kJ/mol while that of olaparib was -159.16 kJ/mol. These results indicated ZINC67913374 bound to PARP1 with a higher affinity, which suggest ZINC67913374 has promising potential for cancer drug development.
authors.affiliation: School of Medicine, Chengdu University, Chengdu 610106, China. lijian01@cdu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: College of Life Sciences and Key Laboratory for Bio-Resources of Ministry of Education, Sichuan University, Chengdu 610064, China. zhnanx@live.com.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhou
authors.affiliation: School of Medicine, Chengdu University, Chengdu 610106, China. caipeiling@cdu.edu.cn.
authors.forename: Peiling
authors.initials: P
authors.lastname: Cai
authors.affiliation: College of Life Sciences and Key Laboratory for Bio-Resources of Ministry of Education, Sichuan University, Chengdu 610064, China. baojinku@scu.edu.cn.
authors.forename: Jinku
authors.initials: J
authors.lastname: Bao
mesh_terms: D001665:Binding Sites; D016923:Cell Death; D003198:Computer Simulation; D004187:Disaccharides / Q000737:chemistry* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology*; D010793:Phthalazines / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000737:chemistry* / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004187:Disaccharides; D010636:Phenols; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C000612062:ZINC67913374; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; C531550:olaparib
keywords: DNA damage response (DDR); PARP inhibitor; synthetic lethality