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Novel PARP-1 Inhibitor Scaffolds Disclosed by a Dynamic Structure-Based Pharmacophore Approach.
PLoS One. 2017; 12(1):e0170846.Plos

Abstract

PARP-1 inhibition has been studied over the last decades for the treatment of various diseases. Despite the fact that several molecules act as PARP-1 inhibitors, a reduced number of compounds are used in clinical practice. To identify new compounds with a discriminatory PARP-1 inhibitory function, explicit-solvent molecular dynamics simulations using different inhibitors bound to the PARP-1 catalytic domain were performed. The representative structures obtained were used to generate structure-based pharmacophores, taking into account the dynamic features of receptor-ligand interactions. Thereafter, a virtual screening of compound databases using the pharmacophore models obtained was performed and the hits retrieved were subjected to molecular docking-based scoring. The drug-like molecules featuring the best ranking were evaluated for their PARP-1 inhibitory activity and IC50 values were calculated for the top scoring docked compounds. Altogether, three new PARP-1 inhibitor chemotypes were identified.

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Authors+Show Affiliations

Baptista SJ
Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Silva MM
Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Moroni E
Istituto di Chimica del Riconoscimento Molecolare, CNR, Milano, Italy.
Meli M
Istituto di Chimica del Riconoscimento Molecolare, CNR, Milano, Italy.
Colombo G
Istituto di Chimica del Riconoscimento Molecolare, CNR, Milano, Italy.
Dinis TC
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.
Salvador JA
Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

MeSH

Catalytic DomainDatabases, PharmaceuticalHumansLigandsModels, MolecularMolecular Docking SimulationMolecular Dynamics SimulationPoly (ADP-Ribose) Polymerase-1Protein BindingStructure-Activity Relationship

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28122037

Citation

Baptista, Salete J., et al. "Novel PARP-1 Inhibitor Scaffolds Disclosed By a Dynamic Structure-Based Pharmacophore Approach." PloS One, vol. 12, no. 1, 2017, pp. e0170846.
Baptista SJ, Silva MM, Moroni E, et al. Novel PARP-1 Inhibitor Scaffolds Disclosed by a Dynamic Structure-Based Pharmacophore Approach. PLoS One. 2017;12(1):e0170846.
Baptista, S. J., Silva, M. M., Moroni, E., Meli, M., Colombo, G., Dinis, T. C., & Salvador, J. A. (2017). Novel PARP-1 Inhibitor Scaffolds Disclosed by a Dynamic Structure-Based Pharmacophore Approach. PloS One, 12(1), e0170846. https://doi.org/10.1371/journal.pone.0170846
Baptista SJ, et al. Novel PARP-1 Inhibitor Scaffolds Disclosed By a Dynamic Structure-Based Pharmacophore Approach. PLoS One. 2017;12(1):e0170846. PubMed PMID: 28122037.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel PARP-1 Inhibitor Scaffolds Disclosed by a Dynamic Structure-Based Pharmacophore Approach. AU - Baptista,Salete J, AU - Silva,Maria M C, AU - Moroni,Elisabetta, AU - Meli,Massimiliano, AU - Colombo,Giorgio, AU - Dinis,Teresa C P, AU - Salvador,Jorge A R, Y1 - 2017/01/25/ PY - 2016/10/08/received PY - 2017/01/11/accepted PY - 2017/1/26/entrez PY - 2017/1/26/pubmed PY - 2017/8/10/medline SP - e0170846 EP - e0170846 JF - PloS one JO - PLoS One VL - 12 IS - 1 N2 - PARP-1 inhibition has been studied over the last decades for the treatment of various diseases. Despite the fact that several molecules act as PARP-1 inhibitors, a reduced number of compounds are used in clinical practice. To identify new compounds with a discriminatory PARP-1 inhibitory function, explicit-solvent molecular dynamics simulations using different inhibitors bound to the PARP-1 catalytic domain were performed. The representative structures obtained were used to generate structure-based pharmacophores, taking into account the dynamic features of receptor-ligand interactions. Thereafter, a virtual screening of compound databases using the pharmacophore models obtained was performed and the hits retrieved were subjected to molecular docking-based scoring. The drug-like molecules featuring the best ranking were evaluated for their PARP-1 inhibitory activity and IC50 values were calculated for the top scoring docked compounds. Altogether, three new PARP-1 inhibitor chemotypes were identified. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/28122037/Novel_PARP_1_Inhibitor_Scaffolds_Disclosed_by_a_Dynamic_Structure_Based_Pharmacophore_Approach_ DB - PRIME DP - Unbound Medicine ER -