title: Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling.
abstract: We disclose herein our efforts aimed at discovery of selective PARP-1 and PARP-2 inhibitors. We have recently discovered several novel classes of quinazolinones, quinazolidinones, and quinoxalines as potent PARP-1 inhibitors, which may represent attractive therapeutic candidates. In PARP enzyme assays using recombinant PARP-1 and PARP-2, the quinazolinone derivatives displayed relatively high selectivity for PARP-1 and quinoxaline derivatives showed superior selectivity for PARP-2, and the quinazolidinone derivatives did not have selectivity for PARP-1/2. Structure-based drug design analysis via a combination of X-ray structural study utilizing the complexes of inhibitors and human PARP-1 catalytic domain, and homology modeling using murine PARP-2 suggested distinct interactions of inhibitors with PARP-1 and PARP-2. These findings provide a new structural framework for the design of selective inhibitors for PARP-1 and PARP-2.
authors.affiliation: Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co. Ltd, Tsukuba, Ibaraki, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Ishida
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kido
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kamijo
authors.forename: Kenji
authors.initials: K
authors.lastname: Murano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyake
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohkubo
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Masaichi
authors.initials: M
authors.lastname: Warizaya
authors.forename: Akinori
authors.initials: A
authors.lastname: Iwashita
authors.forename: Kayoko
authors.initials: K
authors.lastname: Mihara
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
authors.forename: Kouji
authors.initials: K
authors.lastname: Hattori
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D011810:Quinoxalines; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases