title: Free energy calculation provides insight into the action mechanism of selective PARP-1 inhibitor.
abstract: Selective poly (ADP-ribose) polymerase (PARP)-1 inhibitor represents promising therapy against cancers with a good balance between efficacy and safety. Owing to the conserved structure between PARP-1 and PARP-2, most of the clinical and experimental drugs show equivalent inhibition against both targets. Most recently, it's disclosed a highly selective PARP-1 inhibitor (NMS-P118) with promising pharmacokinetic properties. Herein, we combined molecular simulation with free energy calculation to gain insights into the selective mechanism of NMS-P118. Our results suggest the reduction of binding affinity for PARP-2 is attributed to the unfavorable conformational change of protein, which is accompanied by a significant energy penalty. Alanine-scanning mutagenesis study further reveals the important role for a tyrosine residue of donor loop (Tyr889(PARP-1) and Tyr455(PARP-2)) in contributing to the ligand selectivity. Retrospective structural analysis indicates the ligand-induced movement of Tyr455(PARP-2) disrupts the intra-molecule hydrogen bonding network, which partially accounts for the "high-energy" protein conformation in the presence of NMS-P118. Interestingly, such effect isn't observed in other non-selective PARP inhibitors including BMN673 and A861695, which validates the computational prediction. Our work provides energetic insight into the subtle variations in the crystal structures and could facilitate rational design of new selective PARP inhibitor.
authors.affiliation: Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 1 Xian Nong Tan Street, Beijing, 100050, China. caoran@imm.ac.cn.
authors.forename: Ran
authors.initials: R
authors.lastname: Cao
mesh_terms: D020816:Amino Acid Motifs; D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D054833:Isoindoles / Q000737:chemistry*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010880:Piperidines / Q000737:chemistry*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry*; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D054833:Isoindoles; D008024:Ligands; C000603349:NMS-P118; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: Alanine-scanning; Conformational change; Crystal structure; Free energy calculation; PARP; Selective inhibitor