Identification of novel PARP-1 inhibitors by structure-based virtual screening.
Poly(ADP-ribose)polymerase-1 (PARP-1) is an abundant and ubiquitous chromatin-bound nuclear protein. PARP-1, a DNA repair enzyme, has been in the limelight as a chemotherapeutic target. In this study, we demonstrated the successful use of structure-based virtual screening to identify inhibitors of PARP-1 from Otava databases comprised of nearly 260,000 compounds. Five novel inhibitors belonging to thienopyrimidinone, isoquinolinoquinazolinone, pyrroloquinazolinone, and cyclopentenothienopyrimidinone scaffolds revealed inhibitory potencies with IC50 values ranged from 9.57μM to 0.72μM. Structural features relevant to the activity of these novel compounds within the active site of PARP-1 are discussed in detail and will guide future SAR investigation on these scaffolds.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Kevin
K
Hannigan
Shridhar S
SS
Kulkarni
Volodymyr G
VG
Bdzhola
Andriy G
AG
Golub
Sergiy M
SM
Yarmoluk
Tanaji T
TT
Talele
D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D052999:Quinazolinones / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011743:Pyrimidines; D052999:Quinazolinones; C476003:thienopyrimidine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
Cyclopentenothienopyrimidinone; Docking; Isoquinolinoquinazolinone; PARP-1; Thienopyrimidinone; Virtual screening