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Identification of novel PARP-1 inhibitors by structure-based virtual screening.
Bioorg Med Chem Lett. 2013 Nov 01; 23(21):5790-4.BM

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.

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Authors+Show Affiliations

Hannigan K
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Kulkarni SS
No affiliation info available
Bdzhola VG
No affiliation info available
Golub AG
No affiliation info available
Yarmoluk SM
No affiliation info available
Talele TT
No affiliation info available

MeSH

Catalytic DomainDrug DesignEnzyme InhibitorsHumansMolecular Docking SimulationPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesPyrimidinesQuinazolinonesStructure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24074844

Citation

Hannigan, Kevin, et al. "Identification of Novel PARP-1 Inhibitors By Structure-based Virtual Screening." Bioorganic & Medicinal Chemistry Letters, vol. 23, no. 21, 2013, pp. 5790-4.
Hannigan K, Kulkarni SS, Bdzhola VG, et al. Identification of novel PARP-1 inhibitors by structure-based virtual screening. Bioorg Med Chem Lett. 2013;23(21):5790-4.
Hannigan, K., Kulkarni, S. S., Bdzhola, V. G., Golub, A. G., Yarmoluk, S. M., & Talele, T. T. (2013). Identification of novel PARP-1 inhibitors by structure-based virtual screening. Bioorganic & Medicinal Chemistry Letters, 23(21), 5790-4. https://doi.org/10.1016/j.bmcl.2013.09.007
Hannigan K, et al. Identification of Novel PARP-1 Inhibitors By Structure-based Virtual Screening. Bioorg Med Chem Lett. 2013 Nov 1;23(21):5790-4. PubMed PMID: 24074844.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of novel PARP-1 inhibitors by structure-based virtual screening. AU - Hannigan,Kevin, AU - Kulkarni,Shridhar S, AU - Bdzhola,Volodymyr G, AU - Golub,Andriy G, AU - Yarmoluk,Sergiy M, AU - Talele,Tanaji T, Y1 - 2013/09/10/ PY - 2013/07/04/received PY - 2013/08/30/revised PY - 2013/09/03/accepted PY - 2013/10/1/entrez PY - 2013/10/1/pubmed PY - 2014/5/3/medline KW - Cyclopentenothienopyrimidinone KW - Docking KW - Isoquinolinoquinazolinone KW - PARP-1 KW - Thienopyrimidinone KW - Virtual screening SP - 5790 EP - 4 JF - Bioorganic & medicinal chemistry letters JO - Bioorg Med Chem Lett VL - 23 IS - 21 N2 - 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. SN - 1464-3405 UR - https://www.unboundmedicine.com/medline/citation/24074844/Identification_of_novel_PARP_1_inhibitors_by_structure_based_virtual_screening_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-894X(13)01070-6 DB - PRIME DP - Unbound Medicine ER -