title: Docking study and binding free energy calculation of poly (ADP-ribose) polymerase inhibitors.
abstract: Recently, the massively parallel computation of absolute binding free energy with a well-equilibrated system (MP-CAFEE) has been developed. The present study aimed to determine whether the MP-CAFEE method is useful for drug discovery research. In the drug discovery process, it is important for computational chemists to predict the binding affinity accurately without detailed structural information for protein/ligand complex. We investigated the absolute binding free energies for Poly (ADP-ribose) polymerase-1 (PARP-1)/inhibitor complexes, using the MP-CAFEE method. Although each docking model was used as an input structure, it was found that the absolute binding free energies calculated by MP-CAFEE are well consistent with the experimental ones. The accuracy of this method is much higher than that using molecular mechanics Poisson-Boltzmann/surface area (MM/PBSA). Although the simulation time is quite extensive, the reliable predictor of binding free energies would be a useful tool for drug discovery projects.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ohno
authors.forename: Takashi
authors.initials: T
authors.lastname: Mitsui
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tanida
authors.forename: Azuma
authors.initials: A
authors.lastname: Matsuura
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujitani
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Niimi
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases