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Probing PARP1-inhibitor complexes for the development of novel inhibitors.
Cell Mol Biol (Noisy-le-grand). 2014 Oct 25; 60(3):43-52.CM

Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) is the most important member of the PARP family which has been shown to have a direct involvement in the development of cancer. A strategy to rationalize the structure based drug discovery of PARP1 inhibitors has been discussed. So far studies regarding varied scaffold PARP1 inhibitors have been done, however the current study focus on how the available data from potent PARP1 inhibitors could be combined and utilized for developing a robust model for the development of novel inhibitors. Through detailed analyses of PARP1-inhibitor binding, a pharmacophore model has been developed followed by a virtual screen of potential inhibitors. The resulting high-affinity binding hits following the defined pharmacophore model and making the critical interactions were selected as final potential leads. Hence, using the approaches of pharmacophore design, docking based virtual screening and conformation alignment, we have identified important leads which satisfy all parameters of the screening process. The developed pharmacophore model as well as the strategy is very straightforward for screening novel inhibitors and could thus be used as a prototype for PARP1 structure based drug discovery.

Authors+Show Affiliations

Saqib U
Maulana Azad National Institute of Technology (MANIT) Department of Mathematics Madhya Pradesh India.
Baig MS
University of Illinois at Chicago (UIC) Department of Medicine Chicago USA msb.uicmed@gmail.com.

MeSH

BenzimidazolesDrug DesignEnzyme InhibitorsModels, MolecularMolecular ConformationMolecular Docking SimulationPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesProtein Interaction Mapping

Pub Type(s)

Journal Article

Language

eng

PubMed ID

25346248

Citation

Saqib, U, and M S. Baig. "Probing PARP1-inhibitor Complexes for the Development of Novel Inhibitors." Cellular and Molecular Biology (Noisy-le-Grand, France), vol. 60, no. 3, 2014, pp. 43-52.
Saqib U, Baig MS. Probing PARP1-inhibitor complexes for the development of novel inhibitors. Cell Mol Biol (Noisy-le-grand). 2014;60(3):43-52.
Saqib, U., & Baig, M. S. (2014). Probing PARP1-inhibitor complexes for the development of novel inhibitors. Cellular and Molecular Biology (Noisy-le-Grand, France), 60(3), 43-52.
Saqib U, Baig MS. Probing PARP1-inhibitor Complexes for the Development of Novel Inhibitors. Cell Mol Biol (Noisy-le-grand). 2014 Oct 25;60(3):43-52. PubMed PMID: 25346248.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Probing PARP1-inhibitor complexes for the development of novel inhibitors. AU - Saqib,U, AU - Baig,M S, Y1 - 2014/10/25/ PY - 2014/08/27/received PY - 2014/10/17/accepted PY - 2014/10/28/entrez PY - 2014/10/28/pubmed PY - 2015/7/17/medline SP - 43 EP - 52 JF - Cellular and molecular biology (Noisy-le-Grand, France) JO - Cell Mol Biol (Noisy-le-grand) VL - 60 IS - 3 N2 - Poly (ADP-ribose) polymerase 1 (PARP1) is the most important member of the PARP family which has been shown to have a direct involvement in the development of cancer. A strategy to rationalize the structure based drug discovery of PARP1 inhibitors has been discussed. So far studies regarding varied scaffold PARP1 inhibitors have been done, however the current study focus on how the available data from potent PARP1 inhibitors could be combined and utilized for developing a robust model for the development of novel inhibitors. Through detailed analyses of PARP1-inhibitor binding, a pharmacophore model has been developed followed by a virtual screen of potential inhibitors. The resulting high-affinity binding hits following the defined pharmacophore model and making the critical interactions were selected as final potential leads. Hence, using the approaches of pharmacophore design, docking based virtual screening and conformation alignment, we have identified important leads which satisfy all parameters of the screening process. The developed pharmacophore model as well as the strategy is very straightforward for screening novel inhibitors and could thus be used as a prototype for PARP1 structure based drug discovery. SN - 1165-158X UR - https://www.unboundmedicine.com/medline/citation/25346248/Probing_PARP1_inhibitor_complexes_for_the_development_of_novel_inhibitors_ DB - PRIME DP - Unbound Medicine ER -