Structure-based design of novel human Pin1 inhibitors (II)
A series of non-phosphate small molecular Pin1 inhibitors was discovered utilizing SBDD approach. The structure–activity relationship of phosphate replacement groups was investigated. Following the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design s...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2010-04, Vol.20 (7), p.2210-2214 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Dong, Liming Marakovits, Joseph Hou, Xinjun Guo, Chuangxing Greasley, Samantha Dagostino, Eleanor Ferre, RoseAnn Johnson, M. Catherine Kraynov, Eugenia Thomson, James Pathak, Ved Murray, Brion W. |
| description | A series of non-phosphate small molecular Pin1 inhibitors was discovered utilizing SBDD approach. The structure–activity relationship of phosphate replacement groups was investigated.
Following the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design strategy shifted to replacement of the phosphate group with an isostere with potential better pharmaceutical properties. The initial loss in potency of carboxylate analogs was likely due to weaker charge–charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand–protein interactions in the proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor. |
| doi_str_mv | 10.1016/j.bmcl.2010.02.033 |
| format | Article |
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Following the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design strategy shifted to replacement of the phosphate group with an isostere with potential better pharmaceutical properties. The initial loss in potency of carboxylate analogs was likely due to weaker charge–charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand–protein interactions in the proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2010.02.033</identifier><identifier>PMID: 20207139</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>Anti-cancer agents ; Antineoplastic agents ; Binding Sites ; Biological and medical sciences ; Carboxylates ; Crystallography, X-Ray ; Drug Design ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; General aspects ; Humans ; Medical sciences ; Models, Molecular ; NIMA-Interacting Peptidylprolyl Isomerase ; Peptidylprolyl Isomerase - antagonists & inhibitors ; Peptidylprolyl Isomerase - chemistry ; Peptidylprolyl Isomerase - metabolism ; Pharmacology. Drug treatments ; Phosphate replacement ; Pin1 ; Pin1 inhibitors ; PPIase ; Protein Binding ; SBDD ; Structure-Activity Relationship ; Tetrazoles</subject><ispartof>Bioorganic & medicinal chemistry letters, 2010-04, Vol.20 (7), p.2210-2214</ispartof><rights>2010 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>2010 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-c7e88d21fb9e8eb9929e5a0c637e1f063068392825911a191f3d16c5a43e35e43</citedby><cites>FETCH-LOGICAL-c417t-c7e88d21fb9e8eb9929e5a0c637e1f063068392825911a191f3d16c5a43e35e43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2010.02.033$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,778,782,3539,27907,27908,45978</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22824884$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20207139$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dong, Liming</creatorcontrib><creatorcontrib>Marakovits, Joseph</creatorcontrib><creatorcontrib>Hou, Xinjun</creatorcontrib><creatorcontrib>Guo, Chuangxing</creatorcontrib><creatorcontrib>Greasley, Samantha</creatorcontrib><creatorcontrib>Dagostino, Eleanor</creatorcontrib><creatorcontrib>Ferre, RoseAnn</creatorcontrib><creatorcontrib>Johnson, M. Catherine</creatorcontrib><creatorcontrib>Kraynov, Eugenia</creatorcontrib><creatorcontrib>Thomson, James</creatorcontrib><creatorcontrib>Pathak, Ved</creatorcontrib><creatorcontrib>Murray, Brion W.</creatorcontrib><title>Structure-based design of novel human Pin1 inhibitors (II)</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A series of non-phosphate small molecular Pin1 inhibitors was discovered utilizing SBDD approach. The structure–activity relationship of phosphate replacement groups was investigated.
Following the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design strategy shifted to replacement of the phosphate group with an isostere with potential better pharmaceutical properties. The initial loss in potency of carboxylate analogs was likely due to weaker charge–charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand–protein interactions in the proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor.</description><subject>Anti-cancer agents</subject><subject>Antineoplastic agents</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Carboxylates</subject><subject>Crystallography, X-Ray</subject><subject>Drug Design</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>General aspects</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>NIMA-Interacting Peptidylprolyl Isomerase</subject><subject>Peptidylprolyl Isomerase - antagonists & inhibitors</subject><subject>Peptidylprolyl Isomerase - chemistry</subject><subject>Peptidylprolyl Isomerase - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphate replacement</subject><subject>Pin1</subject><subject>Pin1 inhibitors</subject><subject>PPIase</subject><subject>Protein Binding</subject><subject>SBDD</subject><subject>Structure-Activity Relationship</subject><subject>Tetrazoles</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1P3DAQhq2qFSzQP9BDlUsFHLLM2I4TV1wQ4mMlpFYCJG6W40yKV_mgdoLEvyfRbuFGTyONnvfVzMPYN4QlAqqT9bJsXbPkMC2AL0GIT2yBUslUSMg-swVoBWmh5cMu24txDYASpNxhuxw45Cj0gv28HcLohjFQWtpIVVJR9H-6pK-Trn-mJnkcW9slv32Hie8efemHPsTkaLU6PmBfattE-rqd--z-8uLu_Dq9-XW1Oj-7SZ3EfEhdTkVRcaxLTQWVWnNNmQWnRE5YgxKgCqF5wTONaFFjLSpULrNSkMhIin12uOl9Cv3fkeJgWh8dNY3tqB-jyaUCUJnQ_yeFUEJmOJN8Q7rQxxioNk_Btza8GAQzyzVrM8s1s1wD3Exyp9D3bf1YtlS9Rf7ZnIAfW8BGZ5s62M75-M5NT8qimD863XA0aXv2FEx0njpHlQ_kBlP1_qM7XgEed5Sy</recordid><startdate>20100401</startdate><enddate>20100401</enddate><creator>Dong, Liming</creator><creator>Marakovits, Joseph</creator><creator>Hou, Xinjun</creator><creator>Guo, Chuangxing</creator><creator>Greasley, Samantha</creator><creator>Dagostino, Eleanor</creator><creator>Ferre, RoseAnn</creator><creator>Johnson, M. Catherine</creator><creator>Kraynov, Eugenia</creator><creator>Thomson, James</creator><creator>Pathak, Ved</creator><creator>Murray, Brion W.</creator><general>Elsevier Ltd</general><general>Elsevier</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><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20100401</creationdate><title>Structure-based design of novel human Pin1 inhibitors (II)</title><author>Dong, Liming ; Marakovits, Joseph ; Hou, Xinjun ; Guo, Chuangxing ; Greasley, Samantha ; Dagostino, Eleanor ; Ferre, RoseAnn ; Johnson, M. 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Drug treatments</topic><topic>Phosphate replacement</topic><topic>Pin1</topic><topic>Pin1 inhibitors</topic><topic>PPIase</topic><topic>Protein Binding</topic><topic>SBDD</topic><topic>Structure-Activity Relationship</topic><topic>Tetrazoles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dong, Liming</creatorcontrib><creatorcontrib>Marakovits, Joseph</creatorcontrib><creatorcontrib>Hou, Xinjun</creatorcontrib><creatorcontrib>Guo, Chuangxing</creatorcontrib><creatorcontrib>Greasley, Samantha</creatorcontrib><creatorcontrib>Dagostino, Eleanor</creatorcontrib><creatorcontrib>Ferre, RoseAnn</creatorcontrib><creatorcontrib>Johnson, M. 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Following the discovery of a novel series of phosphate-containing small molecular Pin1 inhibitors, the drug design strategy shifted to replacement of the phosphate group with an isostere with potential better pharmaceutical properties. The initial loss in potency of carboxylate analogs was likely due to weaker charge–charge interactions in the putative phosphate binding pocket and was subsequently recovered by structure-based optimization of ligand–protein interactions in the proline binding site, leading to the discovery of a sub-micromolar non-phosphate small molecular Pin1 inhibitor.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>20207139</pmid><doi>10.1016/j.bmcl.2010.02.033</doi><tpages>5</tpages></addata></record> |
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| subjects | Anti-cancer agents Antineoplastic agents Binding Sites Biological and medical sciences Carboxylates Crystallography, X-Ray Drug Design Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology General aspects Humans Medical sciences Models, Molecular NIMA-Interacting Peptidylprolyl Isomerase Peptidylprolyl Isomerase - antagonists & inhibitors Peptidylprolyl Isomerase - chemistry Peptidylprolyl Isomerase - metabolism Pharmacology. Drug treatments Phosphate replacement Pin1 Pin1 inhibitors PPIase Protein Binding SBDD Structure-Activity Relationship Tetrazoles |
| title | Structure-based design of novel human Pin1 inhibitors (II) |
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