Structure-based approach to nanomolar, water soluble matrix metalloproteinases inhibitors (MMPIs)
N-Arylsulfonyl-based MMPs inhibitors (MMPIs) are among the most prominent inhibitors possessing nanomolar affinity. However, their poor bioavailability remains critical for the drug development of this family of molecules. The structural analysis of the complex of NNGH (the most representative membe...
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| Veröffentlicht in: | European journal of medicinal chemistry 2010-12, Vol.45 (12), p.5919-5925 |
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| container_title | European journal of medicinal chemistry |
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| creator | Attolino, Emanuele Calderone, Vito Dragoni, Elisa Fragai, Marco Richichi, Barbara Luchinat, Claudio Nativi, Cristina |
| description | N-Arylsulfonyl-based MMPs inhibitors (MMPIs) are among the most prominent inhibitors possessing nanomolar affinity. However, their poor bioavailability remains critical for the drug development of this family of molecules. The structural analysis of the complex of NNGH (the most representative member of the family) with MMP-12 provided us with the basis to effectively design simple NNGH analogues with enhanced solubility in water. Following this approach, the sec-butyl residue, not directly involved in the binding with MMP, has been replaced with hydrophilic residues thus yielding new potent inhibitors soluble in water.
Sulfonamidic MMPs inhibitors soluble in water were obtained relying on structural-based approach. This new family of large spectrum, nanomolar inhibitors can be seen as water soluble NNGH analogues.
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| doi_str_mv | 10.1016/j.ejmech.2010.09.057 |
| format | Article |
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Sulfonamidic MMPs inhibitors soluble in water were obtained relying on structural-based approach. This new family of large spectrum, nanomolar inhibitors can be seen as water soluble NNGH analogues.
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Sulfonamidic MMPs inhibitors soluble in water were obtained relying on structural-based approach. This new family of large spectrum, nanomolar inhibitors can be seen as water soluble NNGH analogues.
[Display omitted]</description><subject>Analytical, structural and metabolic biochemistry</subject><subject>Biological and medical sciences</subject><subject>Crystallography, X-Ray</subject><subject>Enzymes and enzyme inhibitors</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Hydrolases</subject><subject>Inhibitors</subject><subject>Matrix Metalloproteinase Inhibitors</subject><subject>Medical sciences</subject><subject>Metalloproteinases</subject><subject>Miscellaneous</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Nanostructures - chemistry</subject><subject>Pharmacology. Drug treatments</subject><subject>Protease Inhibitors - chemical synthesis</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Solubility</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Structure-based approach</subject><subject>Substituent effect</subject><subject>Sulfonamides</subject><subject>Sulfones - chemical synthesis</subject><subject>Sulfones - chemistry</subject><subject>Sulfones - pharmacology</subject><subject>Water - chemistry</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kFuLFDEQRoMo7uzqPxDJi7iCPVZufXkRZPGysIuC-hzSSTWTId0Zk7SXf2-WGfXNp4Jwvqovh5AnDLYMWPtqv8X9jHa35VCfYNiC6u6RDevavhFcyftkA5yLRnEhz8h5znsAUC3AQ3LGYWhVy2FDzOeSVlvWhM1oMjpqDocUjd3REuliljjHYNJL-sMUTDTHsI4B6WxK8j_pjMWEEGugoF9qPFO_7PzoS0yZXt7efrrOLx6RB5MJGR-f5gX5-u7tl6sPzc3H99dXb24aK1VXGja1oAYmBi6lQCXZNNZPWCfRjf3IanHlJlBqQtG6bmw75hBtJ50F0WPPxQV5ftxb63xbMRc9-2wxBLNgXLPuGWeirukqKY-kTTHnhJM-JD-b9Esz0Hdu9V4f3eo7txoGXd3W2NPTgXWc0f0N_ZFZgWcnwGRrwpTMYn3-xwnZSdbLyr0-clh1fPeYdLYeF4vOJ7RFu-j_3-Q3unaaGA</recordid><startdate>20101201</startdate><enddate>20101201</enddate><creator>Attolino, Emanuele</creator><creator>Calderone, Vito</creator><creator>Dragoni, Elisa</creator><creator>Fragai, Marco</creator><creator>Richichi, Barbara</creator><creator>Luchinat, Claudio</creator><creator>Nativi, Cristina</creator><general>Elsevier Masson SAS</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></search><sort><creationdate>20101201</creationdate><title>Structure-based approach to nanomolar, water soluble matrix metalloproteinases inhibitors (MMPIs)</title><author>Attolino, Emanuele ; Calderone, Vito ; Dragoni, Elisa ; Fragai, Marco ; Richichi, Barbara ; Luchinat, Claudio ; Nativi, Cristina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c457t-1f60591392443e541fb254cd4edb8b15605df055fe36d7b671deec74dc038e823</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Analytical, structural and metabolic biochemistry</topic><topic>Biological and medical sciences</topic><topic>Crystallography, X-Ray</topic><topic>Enzymes and enzyme inhibitors</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Hydrolases</topic><topic>Inhibitors</topic><topic>Matrix Metalloproteinase Inhibitors</topic><topic>Medical sciences</topic><topic>Metalloproteinases</topic><topic>Miscellaneous</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Nanostructures - chemistry</topic><topic>Pharmacology. Drug treatments</topic><topic>Protease Inhibitors - chemical synthesis</topic><topic>Protease Inhibitors - chemistry</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Solubility</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Structure-based approach</topic><topic>Substituent effect</topic><topic>Sulfonamides</topic><topic>Sulfones - chemical synthesis</topic><topic>Sulfones - chemistry</topic><topic>Sulfones - pharmacology</topic><topic>Water - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Attolino, Emanuele</creatorcontrib><creatorcontrib>Calderone, Vito</creatorcontrib><creatorcontrib>Dragoni, Elisa</creatorcontrib><creatorcontrib>Fragai, Marco</creatorcontrib><creatorcontrib>Richichi, Barbara</creatorcontrib><creatorcontrib>Luchinat, Claudio</creatorcontrib><creatorcontrib>Nativi, Cristina</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>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Attolino, Emanuele</au><au>Calderone, Vito</au><au>Dragoni, Elisa</au><au>Fragai, Marco</au><au>Richichi, Barbara</au><au>Luchinat, Claudio</au><au>Nativi, Cristina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-based approach to nanomolar, water soluble matrix metalloproteinases inhibitors (MMPIs)</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2010-12-01</date><risdate>2010</risdate><volume>45</volume><issue>12</issue><spage>5919</spage><epage>5925</epage><pages>5919-5925</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><coden>EJMCA5</coden><abstract>N-Arylsulfonyl-based MMPs inhibitors (MMPIs) are among the most prominent inhibitors possessing nanomolar affinity. However, their poor bioavailability remains critical for the drug development of this family of molecules. The structural analysis of the complex of NNGH (the most representative member of the family) with MMP-12 provided us with the basis to effectively design simple NNGH analogues with enhanced solubility in water. Following this approach, the sec-butyl residue, not directly involved in the binding with MMP, has been replaced with hydrophilic residues thus yielding new potent inhibitors soluble in water.
Sulfonamidic MMPs inhibitors soluble in water were obtained relying on structural-based approach. This new family of large spectrum, nanomolar inhibitors can be seen as water soluble NNGH analogues.
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| subjects | Analytical, structural and metabolic biochemistry Biological and medical sciences Crystallography, X-Ray Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology Hydrolases Inhibitors Matrix Metalloproteinase Inhibitors Medical sciences Metalloproteinases Miscellaneous Models, Molecular Molecular Structure Nanostructures - chemistry Pharmacology. Drug treatments Protease Inhibitors - chemical synthesis Protease Inhibitors - chemistry Protease Inhibitors - pharmacology Solubility Stereoisomerism Structure-Activity Relationship Structure-based approach Substituent effect Sulfonamides Sulfones - chemical synthesis Sulfones - chemistry Sulfones - pharmacology Water - chemistry |
| title | Structure-based approach to nanomolar, water soluble matrix metalloproteinases inhibitors (MMPIs) |
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