Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling
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 assa...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2006-03, Vol.14 (5), p.1378-1390 |
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| creator | Ishida, Junya Yamamoto, Hirofumi Kido, Yoshiyuki Kamijo, Kazunori Murano, Kenji Miyake, Hiroshi Ohkubo, Mitsuru Kinoshita, Takayoshi Warizaya, Masaichi Iwashita, Akinori Mihara, Kayoko Matsuoka, Nobuya Hattori, Kouji |
| description | 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. |
| doi_str_mv | 10.1016/j.bmc.2005.09.061 |
| format | Article |
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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.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2005.09.061</identifier><identifier>PMID: 16288880</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>AD site ; adenine-ribose binding site ; Analytical, structural and metabolic biochemistry ; Binding Sites ; Biological and medical sciences ; Catalytic Domain ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - pharmacology ; Enzymes and enzyme inhibitors ; Fundamental and applied biological sciences. Psychology ; Homology modeling ; Humans ; Medical sciences ; Miscellaneous ; Models, Chemical ; Models, Molecular ; NAD ; NI site ; nicotinamide adenine dinucleotide ; nicotinamide-ribose binding site ; PAR ; PARP-1 ; PARP-2 ; Pharmacology. Drug treatments ; Poly (ADP-Ribose) Polymerase-1 ; poly(ADP-ribose) ; Poly(ADP-ribose) Polymerase Inhibitors ; poly(ADP-ribose) polymerase-2 (PARP-2) ; Poly(ADP-ribose) Polymerases ; Quinazolines - chemical synthesis ; Quinazolines - pharmacology ; Quinoxalines - chemical synthesis ; Quinoxalines - pharmacology ; SBDD ; structure based drug design ; Structure-Activity Relationship ; Transferases ; X-ray</subject><ispartof>Bioorganic & medicinal chemistry, 2006-03, Vol.14 (5), p.1378-1390</ispartof><rights>2005 Elsevier Ltd</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c381t-a98496734c2543586b7f8f600748a468a82b9e677eb5780623262c2bf5c6d0e23</citedby><cites>FETCH-LOGICAL-c381t-a98496734c2543586b7f8f600748a468a82b9e677eb5780623262c2bf5c6d0e23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089605009417$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17555144$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16288880$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ishida, Junya</creatorcontrib><creatorcontrib>Yamamoto, Hirofumi</creatorcontrib><creatorcontrib>Kido, Yoshiyuki</creatorcontrib><creatorcontrib>Kamijo, Kazunori</creatorcontrib><creatorcontrib>Murano, Kenji</creatorcontrib><creatorcontrib>Miyake, Hiroshi</creatorcontrib><creatorcontrib>Ohkubo, Mitsuru</creatorcontrib><creatorcontrib>Kinoshita, Takayoshi</creatorcontrib><creatorcontrib>Warizaya, Masaichi</creatorcontrib><creatorcontrib>Iwashita, Akinori</creatorcontrib><creatorcontrib>Mihara, Kayoko</creatorcontrib><creatorcontrib>Matsuoka, Nobuya</creatorcontrib><creatorcontrib>Hattori, Kouji</creatorcontrib><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</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>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.</description><subject>AD site</subject><subject>adenine-ribose binding site</subject><subject>Analytical, structural and metabolic biochemistry</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Catalytic Domain</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzymes and enzyme inhibitors</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Homology modeling</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Models, Chemical</subject><subject>Models, Molecular</subject><subject>NAD</subject><subject>NI site</subject><subject>nicotinamide adenine dinucleotide</subject><subject>nicotinamide-ribose binding site</subject><subject>PAR</subject><subject>PARP-1</subject><subject>PARP-2</subject><subject>Pharmacology. Drug treatments</subject><subject>Poly (ADP-Ribose) Polymerase-1</subject><subject>poly(ADP-ribose)</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors</subject><subject>poly(ADP-ribose) polymerase-2 (PARP-2)</subject><subject>Poly(ADP-ribose) Polymerases</subject><subject>Quinazolines - chemical synthesis</subject><subject>Quinazolines - pharmacology</subject><subject>Quinoxalines - chemical synthesis</subject><subject>Quinoxalines - pharmacology</subject><subject>SBDD</subject><subject>structure based drug design</subject><subject>Structure-Activity Relationship</subject><subject>Transferases</subject><subject>X-ray</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1TAQhS0EoreFB2CDvKG7hLHjOA6sSi9_UiWqFiR2luNMWl8l8cVOrpSn4JXx_ZG6YzYzsr85Gp1DyBsGOQMm32_yZrA5ByhzqHOQ7BlZMSFFVhQ1e05WUEuVgarlGTmPcQMAXNTsJTljkqtUsCJ_1y5av8OwUN_RrZ9wnKgZWxqxRzu5HdLbq7vbjB0eDyOnbnx0jZt8iB_o_af1Ov2Zfoku0p0z1FDrh8aNZnJ-3Kv-zoJZaJzCbKc5mD6Nc7scBB_94Hv_sNDBt9i78eEVedGZPuLrU78gv758_nn9Lbv58fX79dVNZgvFpszUStSyKoTlpShKJZuqU50EqIQyQiqjeFOjrCpsykqB5AWX3PKmK61sAXlxQS6Putvg_8wYJz0kI7DvzYh-jroCqaSCPciOoA0-xoCd3gY3mLBoBnqfgt7olILep6Ch1imFtPP2JD43A7ZPGyfbE_DuBJhoTd8FM1oXn7iqLEsmROI-HjlMVuwcBh2tw9Fi60JKR7fe_eeMfwRGpBA</recordid><startdate>20060301</startdate><enddate>20060301</enddate><creator>Ishida, Junya</creator><creator>Yamamoto, Hirofumi</creator><creator>Kido, Yoshiyuki</creator><creator>Kamijo, Kazunori</creator><creator>Murano, Kenji</creator><creator>Miyake, Hiroshi</creator><creator>Ohkubo, Mitsuru</creator><creator>Kinoshita, Takayoshi</creator><creator>Warizaya, Masaichi</creator><creator>Iwashita, Akinori</creator><creator>Mihara, Kayoko</creator><creator>Matsuoka, Nobuya</creator><creator>Hattori, Kouji</creator><general>Elsevier Ltd</general><general>Elsevier Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20060301</creationdate><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</title><author>Ishida, Junya ; Yamamoto, Hirofumi ; Kido, Yoshiyuki ; Kamijo, Kazunori ; Murano, Kenji ; Miyake, Hiroshi ; Ohkubo, Mitsuru ; Kinoshita, Takayoshi ; Warizaya, Masaichi ; Iwashita, Akinori ; Mihara, Kayoko ; Matsuoka, Nobuya ; Hattori, Kouji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c381t-a98496734c2543586b7f8f600748a468a82b9e677eb5780623262c2bf5c6d0e23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>AD site</topic><topic>adenine-ribose binding site</topic><topic>Analytical, structural and metabolic biochemistry</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Catalytic Domain</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzymes and enzyme inhibitors</topic><topic>Fundamental and applied biological sciences. 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Drug treatments</topic><topic>Poly (ADP-Ribose) Polymerase-1</topic><topic>poly(ADP-ribose)</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors</topic><topic>poly(ADP-ribose) polymerase-2 (PARP-2)</topic><topic>Poly(ADP-ribose) Polymerases</topic><topic>Quinazolines - chemical synthesis</topic><topic>Quinazolines - pharmacology</topic><topic>Quinoxalines - chemical synthesis</topic><topic>Quinoxalines - pharmacology</topic><topic>SBDD</topic><topic>structure based drug design</topic><topic>Structure-Activity Relationship</topic><topic>Transferases</topic><topic>X-ray</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ishida, Junya</creatorcontrib><creatorcontrib>Yamamoto, Hirofumi</creatorcontrib><creatorcontrib>Kido, Yoshiyuki</creatorcontrib><creatorcontrib>Kamijo, Kazunori</creatorcontrib><creatorcontrib>Murano, Kenji</creatorcontrib><creatorcontrib>Miyake, Hiroshi</creatorcontrib><creatorcontrib>Ohkubo, Mitsuru</creatorcontrib><creatorcontrib>Kinoshita, Takayoshi</creatorcontrib><creatorcontrib>Warizaya, Masaichi</creatorcontrib><creatorcontrib>Iwashita, Akinori</creatorcontrib><creatorcontrib>Mihara, Kayoko</creatorcontrib><creatorcontrib>Matsuoka, Nobuya</creatorcontrib><creatorcontrib>Hattori, Kouji</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ishida, Junya</au><au>Yamamoto, Hirofumi</au><au>Kido, Yoshiyuki</au><au>Kamijo, Kazunori</au><au>Murano, Kenji</au><au>Miyake, Hiroshi</au><au>Ohkubo, Mitsuru</au><au>Kinoshita, Takayoshi</au><au>Warizaya, Masaichi</au><au>Iwashita, Akinori</au><au>Mihara, Kayoko</au><au>Matsuoka, Nobuya</au><au>Hattori, Kouji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of potent and selective PARP-1 and PARP-2 inhibitors: SBDD analysis via a combination of X-ray structural study and homology modeling</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2006-03-01</date><risdate>2006</risdate><volume>14</volume><issue>5</issue><spage>1378</spage><epage>1390</epage><pages>1378-1390</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><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.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>16288880</pmid><doi>10.1016/j.bmc.2005.09.061</doi><tpages>13</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0968-0896 |
| ispartof | Bioorganic & medicinal chemistry, 2006-03, Vol.14 (5), p.1378-1390 |
| issn | 0968-0896 1464-3391 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | AD site adenine-ribose binding site Analytical, structural and metabolic biochemistry Binding Sites Biological and medical sciences Catalytic Domain Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology Homology modeling Humans Medical sciences Miscellaneous Models, Chemical Models, Molecular NAD NI site nicotinamide adenine dinucleotide nicotinamide-ribose binding site PAR PARP-1 PARP-2 Pharmacology. Drug treatments Poly (ADP-Ribose) Polymerase-1 poly(ADP-ribose) Poly(ADP-ribose) Polymerase Inhibitors poly(ADP-ribose) polymerase-2 (PARP-2) Poly(ADP-ribose) Polymerases Quinazolines - chemical synthesis Quinazolines - pharmacology Quinoxalines - chemical synthesis Quinoxalines - pharmacology SBDD structure based drug design Structure-Activity Relationship Transferases X-ray |
| 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 |
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