1. Identification of novel PARP-1 inhibitors by structure-based virtual screening.
- Author
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Hannigan K, Kulkarni SS, Bdzhola VG, Golub AG, Yarmoluk SM, and Talele TT
- Subjects
- Catalytic Domain, Drug Design, Enzyme Inhibitors pharmacology, Humans, Molecular Docking Simulation, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases chemistry, Poly(ADP-ribose) Polymerases metabolism, Pyrimidines pharmacology, Quinazolinones pharmacology, Structure-Activity Relationship, Enzyme Inhibitors chemistry, Poly(ADP-ribose) Polymerase Inhibitors, Pyrimidines chemistry, Quinazolinones chemistry
- Abstract
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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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