title: Multiple receptor conformation docking, dock pose clustering and 3D QSAR studies on human poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.
abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) functions as a DNA damage sensor and signaling molecule. It plays a vital role in the repair of DNA strand breaks induced by radiation and chemotherapeutic drugs; inhibitors of this enzyme have the potential to improve cancer chemotherapy or radiotherapy. Three-dimensional quantitative structure activity relationship (3D QSAR) models were developed using comparative molecular field analysis, comparative molecular similarity indices analysis and docking studies. A set of 88 molecules were docked into the active site of six X-ray crystal structures of poly(ADP-ribose)polymerase-1 (PARP-1), by a procedure called multiple receptor conformation docking (MRCD), in order to improve the 3D QSAR models through the analysis of binding conformations. The docked poses were clustered to obtain the best receptor binding conformation. These dock poses from clustering were used for 3D QSAR analysis. Based on MRCD and QSAR information, some key features have been identified that explain the observed variance in the activity. Two receptor-based QSAR models were generated; these models showed good internal and external statistical reliability that is evident from the [Formula: see text], [Formula: see text] and [Formula: see text]. The identified key features enabled us to design new PARP-1 inhibitors.
authors.affiliation: Department of Chemistry, University College of Science, Osmania University , Hyderabad, Andhra Pradesh , India.
authors.forename: Sabiha
authors.initials: S
authors.lastname: Fatima
authors.forename: Mohan Babu
authors.initials: MB
authors.lastname: Jatavath
authors.forename: Raju
authors.initials: R
authors.lastname: Bathini
authors.forename: Sree Kanth
authors.initials: SK
authors.lastname: Sivan
authors.forename: Vijjulatha
authors.initials: V
authors.lastname: Manga
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000648:ultrastructure*; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: Comparative molecular similarity indices analysis; multiple receptor conformation docking; partial least square analysis; poly(ADP-ribose) polymerase-1; three-dimensional quantitative structure activity relationship