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Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking and Biological Evaluation for Identification of Potential Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors.
Molecules. 2019 Nov 22; 24(23)M

Abstract

Poly (ADP-ribose) polymerase-1 (PARP-1) plays critical roles in many biological processes and is considered as a potential target for anticancer therapy. Although some PARP-1 inhibitors have been reported, their clinical application in cancer therapy is limited by some shortcomings such as weak affinity, low selectivity and adverse side effects. To identify highly potent and selective PARP-1 inhibitors, an integrated protocol that combines pharmacophore mapping, virtual screening and molecular docking was constructed. It was then used as a screening query to identify potent leads with unknown scaffolds from an in-house database. Finally, four retrieved compounds were selected for biological evaluation. Biological testing indicated that the four compounds showed strong inhibitory activities on the PARP-1 (IC50 < 0.2 μM). MTT assay confirmed that compounds 1-4 inhibited the growth of human lung cancer A549 cells in a dose-dependent manner. The obtained compounds from this study may be potential leads for PARP-1 inhibition in the treatment of cancer.

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Authors+Show Affiliations

Zhou Y
Department of Pharmaceutical Analysis, State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Tang S
Department of Pharmaceutical Analysis, State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Chen T
Department of Pharmaceutical Analysis, State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Niu MM
Department of Pharmaceutical Analysis, State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

MeSH

A549 CellsCell ProliferationCell SurvivalComputer SimulationDrug Screening Assays, AntitumorHumansLung NeoplasmsModels, MolecularMolecular Docking SimulationPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsStructure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31766720

Citation

Zhou, Yunjiang, et al. "Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking and Biological Evaluation for Identification of Potential Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors." Molecules (Basel, Switzerland), vol. 24, no. 23, 2019.
Zhou Y, Tang S, Chen T, et al. Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking and Biological Evaluation for Identification of Potential Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors. Molecules. 2019;24(23).
Zhou, Y., Tang, S., Chen, T., & Niu, M. M. (2019). Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking and Biological Evaluation for Identification of Potential Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors. Molecules (Basel, Switzerland), 24(23). https://doi.org/10.3390/molecules24234258
Zhou Y, et al. Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking and Biological Evaluation for Identification of Potential Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors. Molecules. 2019 Nov 22;24(23) PubMed PMID: 31766720.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking and Biological Evaluation for Identification of Potential Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors. AU - Zhou,Yunjiang, AU - Tang,Shi, AU - Chen,Tingting, AU - Niu,Miao-Miao, Y1 - 2019/11/22/ PY - 2019/09/30/received PY - 2019/11/13/revised PY - 2019/11/20/accepted PY - 2019/11/27/entrez PY - 2019/11/27/pubmed PY - 2020/4/9/medline KW - PARP-1 KW - molecular docking KW - pharmacophore modeling KW - virtual screening JF - Molecules (Basel, Switzerland) JO - Molecules VL - 24 IS - 23 N2 - Poly (ADP-ribose) polymerase-1 (PARP-1) plays critical roles in many biological processes and is considered as a potential target for anticancer therapy. Although some PARP-1 inhibitors have been reported, their clinical application in cancer therapy is limited by some shortcomings such as weak affinity, low selectivity and adverse side effects. To identify highly potent and selective PARP-1 inhibitors, an integrated protocol that combines pharmacophore mapping, virtual screening and molecular docking was constructed. It was then used as a screening query to identify potent leads with unknown scaffolds from an in-house database. Finally, four retrieved compounds were selected for biological evaluation. Biological testing indicated that the four compounds showed strong inhibitory activities on the PARP-1 (IC50 < 0.2 μM). MTT assay confirmed that compounds 1-4 inhibited the growth of human lung cancer A549 cells in a dose-dependent manner. The obtained compounds from this study may be potential leads for PARP-1 inhibition in the treatment of cancer. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/31766720/Structure_Based_Pharmacophore_Modeling_Virtual_Screening_Molecular_Docking_and_Biological_Evaluation_for_Identification_of_Potential_Poly__ADP_Ribose__Polymerase_1__PARP_1__Inhibitors_ DB - PRIME DP - Unbound Medicine ER -