Identification of novel PARP-1 inhibitors by structure-based virtual screening |
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Authors: | Kevin Hannigan Shridhar S Kulkarni Volodymyr G Bdzhola Andriy G Golub Sergiy M Yarmoluk Tanaji T Talele |
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Institution: | 1. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, 8000 Utopia Parkway, Queens, NY 11439, USA;2. Department of Medicinal Chemistry, Institute of Molecular Biology and Genetics of the National Academy of Sciences of Ukraine, 150 Zabolotnogo Street, 03680 Kyiv, Ukraine;3. Otava Ltd, 65 Ellerslie Ave., Suite 560, Toronto, ON M2N 1Y1, Canada |
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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 9.57 μM to 0.72 μM. 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. |
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Keywords: | Virtual screening Docking PARP-1 Thienopyrimidinone Isoquinolinoquinazolinone Cyclopentenothienopyrimidinone |
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