Exploring the effect of PARP-1 flexibility in docking studies

被引:16
作者
Antolin, Albert A. [1 ,2 ]
Carotti, Andrea [3 ]
Nuti, Roberto [3 ]
Hakkaya, Aydie [3 ]
Camaioni, Emidio [3 ]
Mestres, Jordi [1 ,2 ]
Pellicciari, Roberto [3 ,4 ]
Macchiarulo, Antonio [3 ]
机构
[1] Hosp del Mar, IMIM, Res Inst, Res Program Biomed Informat GRIB,Chemogen Lab, Barcelona 08003, Catalonia, Spain
[2] Univ Pompeu Fabra, Barcelona 08003, Catalonia, Spain
[3] Univ Perugia, Dipartimento Chim & Tecnol Farmaco, I-06123 Perugia, Italy
[4] TES Pharma Srl, I-06073 Perugia, Italy
关键词
Replica exchange molecular dynamics; PARP; Molecular docking; Virtual screening; MOLECULAR-DYNAMICS; POLY(ADP-RIBOSE) POLYMERASE; INHIBITORS; IDENTIFICATION; BINDING; SIMULATION; INSIGHTS; LIGANDS; FAMILY; CANCER;
D O I
10.1016/j.jmgm.2013.08.006
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
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. (C) 2013 Elsevier Inc. All rights reserved.
引用
收藏
页码:192 / 201
页数:10
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