Exploring the effect of PARP-1 flexibility in docking studies.
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.
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.
Albert A
AA
Antolin
Andrea
A
Carotti
Roberto
R
Nuti
Aydie
A
Hakkaya
Emidio
E
Camaioni
Jordi
J
Mestres
Roberto
R
Pellicciari
Antonio
A
Macchiarulo
D001665:Binding Sites; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D012997:Solvents; D013696:Temperature
D004791:Enzyme Inhibitors; D008024:Ligands; D012997:Solvents; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
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