Exploring the effect of PARP-1 flexibility in docking studies

J Mol Graph Model. 2013 Sep:45:192-201. doi: 10.1016/j.jmgm.2013.08.006. Epub 2013 Sep 3.


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.

Keywords: EF; Molecular docking; PARP; PCA; REMD; RMSD; Replica exchange molecular dynamics; Virtual screening; enrichment factor; poly(ADP-ribose) polymerase; principal components analysis; replica exchange molecular dynamics; root mean square deviation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Humans
  • Hydrogen Bonding
  • Ligands
  • Models, Molecular*
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / chemistry*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Binding
  • Protein Conformation*
  • Solvents
  • Temperature


  • Enzyme Inhibitors
  • Ligands
  • Solvents
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases