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Exploring the effect of PARP-1 flexibility in docking studies.
J Mol Graph Model. 2013 Sep; 45:192-201.JM

Abstract

Poly(ADP-ribose)polymerase-1 (PARP-1) is an enzyme belonging to the ADP-ribosyltransferase family. A large body of works has validated PARP-1 as an attractive drug target for different therapeutic areas, including cancers and ischemia. Accordingly, sampling the conformational space of the enzyme is pivotal to understand its functions and improve structure-based drug discovery approaches. In the first part of this study we apply replica exchange molecular dynamic (REMD) simulations to sample the conformational space of the catalytic domain of PARP-1 in the ligand-bound and unbound forms. In the second part, we assess how and to what extend the emerging enzyme flexibility affects the performance of docking experiments of a library of PARP-1 inhibitors. This study pinpoints a putative key role of conformational shifts of Leu324, Tyr325 and Lys242 in opening an additional binding site pocket that affects the binding of ligands to the catalytic cleft of PARP-1. Furthermore, it highlights the improvement of the enrichment factor of active ligands obtained in docking experiments when using conformations generated with REMD simulations of ligand-bound PARP-1.

Authors+Show Affiliations

Chemogenomics Laboratory, Research Program in Biomedical Informatics (GRIB), IMIM Hospital del Mar Research Institute and Universitat Pompeu Fabra, Doctor Aiguader 88, 08003 Barcelona, Catalonia, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

24056306

Citation

Antolin, Albert A., et al. "Exploring the Effect of PARP-1 Flexibility in Docking Studies." Journal of Molecular Graphics & Modelling, vol. 45, 2013, pp. 192-201.
Antolin AA, Carotti A, Nuti R, et al. Exploring the effect of PARP-1 flexibility in docking studies. J Mol Graph Model. 2013;45:192-201.
Antolin, A. A., Carotti, A., Nuti, R., Hakkaya, A., Camaioni, E., Mestres, J., Pellicciari, R., & Macchiarulo, A. (2013). Exploring the effect of PARP-1 flexibility in docking studies. Journal of Molecular Graphics & Modelling, 45, 192-201. https://doi.org/10.1016/j.jmgm.2013.08.006
Antolin AA, et al. Exploring the Effect of PARP-1 Flexibility in Docking Studies. J Mol Graph Model. 2013;45:192-201. PubMed PMID: 24056306.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exploring the effect of PARP-1 flexibility in docking studies. AU - Antolin,Albert A, AU - Carotti,Andrea, AU - Nuti,Roberto, AU - Hakkaya,Aydie, AU - Camaioni,Emidio, AU - Mestres,Jordi, AU - Pellicciari,Roberto, AU - Macchiarulo,Antonio, Y1 - 2013/09/03/ PY - 2013/05/22/received PY - 2013/07/15/revised PY - 2013/08/06/accepted PY - 2013/9/24/entrez PY - 2013/9/24/pubmed PY - 2014/5/28/medline KW - EF KW - Molecular docking KW - PARP KW - PCA KW - REMD KW - RMSD KW - Replica exchange molecular dynamics KW - Virtual screening KW - enrichment factor KW - poly(ADP-ribose) polymerase KW - principal components analysis KW - replica exchange molecular dynamics KW - root mean square deviation SP - 192 EP - 201 JF - Journal of molecular graphics & modelling JO - J Mol Graph Model VL - 45 N2 - Poly(ADP-ribose)polymerase-1 (PARP-1) is an enzyme belonging to the ADP-ribosyltransferase family. A large body of works has validated PARP-1 as an attractive drug target for different therapeutic areas, including cancers and ischemia. Accordingly, sampling the conformational space of the enzyme is pivotal to understand its functions and improve structure-based drug discovery approaches. In the first part of this study we apply replica exchange molecular dynamic (REMD) simulations to sample the conformational space of the catalytic domain of PARP-1 in the ligand-bound and unbound forms. In the second part, we assess how and to what extend the emerging enzyme flexibility affects the performance of docking experiments of a library of PARP-1 inhibitors. This study pinpoints a putative key role of conformational shifts of Leu324, Tyr325 and Lys242 in opening an additional binding site pocket that affects the binding of ligands to the catalytic cleft of PARP-1. Furthermore, it highlights the improvement of the enrichment factor of active ligands obtained in docking experiments when using conformations generated with REMD simulations of ligand-bound PARP-1. SN - 1873-4243 UR - https://www.unboundmedicine.com/medline/citation/24056306/Exploring_the_effect_of_PARP_1_flexibility_in_docking_studies_ DB - PRIME DP - Unbound Medicine ER -