In silico analyses of essential interactions of iminosugars with the Hex A active site and evaluation of their pharmacological chaperone effects for Tay-Sachs disease
The affinity of a series of iminosugar-based inhibitors exhibiting various ring sizes toward Hex A and their essential interactions with the enzyme active site were investigated. All the Hex A-inhibiting iminosugars tested formed hydrogen bonds with Arg178, Asp322, Tyr421 and Glu462 and had the favo...
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| Veröffentlicht in: | Organic & biomolecular chemistry 2017, Vol.15 (44), p.9297-9304 |
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| creator | Kato, Atsushi Nakagome, Izumi Nakagawa, Shinpei Kinami, Kyoko Adachi, Isao Jenkinson, Sarah F Désiré, Jérôme Blériot, Yves Nash, Robert J Fleet, George W J Hirono, Shuichi |
| description | The affinity of a series of iminosugar-based inhibitors exhibiting various ring sizes toward Hex A and their essential interactions with the enzyme active site were investigated. All the Hex A-inhibiting iminosugars tested formed hydrogen bonds with Arg178, Asp322, Tyr421 and Glu462 and had the favorable cation-π interaction with Trp460. Among them, DMDP amide (6) proved to be the most potent competitive inhibitor with a K
value of 0.041 μM. We analyzed the dynamic properties of both DMDP amide (6) and DNJNAc (1) in aqueous solution using molecular dynamics (MD) calculations; the distance of the interaction between Asp322 and 3-OH and Glu323 and 6-OH was important for stable interactions with Hex A, reducing fluctuations in the plasticity of the active site. DMDP amide (6) dose-dependently increased intracellular Hex A activity in the G269S mutant cells and restored Hex A activity up to approximately 43% of the wild type level; this effect clearly exceeded the border line treatment for Tay-Sachs disease, which is regarded as 10-15% of the wild type level. This is a significantly greater effect than that of pyrimethamine, which is currently in Phase 2 clinical trials. DMDP amide (6), therefore, represents a new promising pharmacological chaperone candidate for the treatment of Tay-Sachs disease. |
| doi_str_mv | 10.1039/c7ob02281f |
| format | Article |
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value of 0.041 μM. We analyzed the dynamic properties of both DMDP amide (6) and DNJNAc (1) in aqueous solution using molecular dynamics (MD) calculations; the distance of the interaction between Asp322 and 3-OH and Glu323 and 6-OH was important for stable interactions with Hex A, reducing fluctuations in the plasticity of the active site. DMDP amide (6) dose-dependently increased intracellular Hex A activity in the G269S mutant cells and restored Hex A activity up to approximately 43% of the wild type level; this effect clearly exceeded the border line treatment for Tay-Sachs disease, which is regarded as 10-15% of the wild type level. This is a significantly greater effect than that of pyrimethamine, which is currently in Phase 2 clinical trials. DMDP amide (6), therefore, represents a new promising pharmacological chaperone candidate for the treatment of Tay-Sachs disease.</description><identifier>ISSN: 1477-0520</identifier><identifier>EISSN: 1477-0539</identifier><identifier>DOI: 10.1039/c7ob02281f</identifier><identifier>PMID: 28959811</identifier><language>eng</language><publisher>England: Royal Society of Chemistry</publisher><subject>Catalysis ; Catalytic Domain ; Chemical bonds ; Chemical Sciences ; Clinical trials ; Computer Simulation ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - metabolism ; Enzyme Inhibitors - pharmacology ; Enzyme Inhibitors - therapeutic use ; Hexosaminidase A - antagonists & inhibitors ; Hexosaminidase A - chemistry ; Hexosaminidase A - genetics ; Hexosaminidase A - metabolism ; Humans ; Hydrogen bonding ; Hydrogen bonds ; Medical research ; Medical treatment ; Molecular dynamics ; Molecular Dynamics Simulation ; Mutation ; Pharmacology ; Pyrimethamine ; Sugars - chemistry ; Sugars - metabolism ; Sugars - pharmacology ; Sugars - therapeutic use ; Tay-Sachs disease ; Tay-Sachs Disease - drug therapy ; Variation</subject><ispartof>Organic & biomolecular chemistry, 2017, Vol.15 (44), p.9297-9304</ispartof><rights>Copyright Royal Society of Chemistry 2017</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c349t-62e33986152d9c670c8740334c877842f49889e7e1a1e25b3c4a25552a5c54083</citedby><cites>FETCH-LOGICAL-c349t-62e33986152d9c670c8740334c877842f49889e7e1a1e25b3c4a25552a5c54083</cites><orcidid>0000-0002-3209-9282 ; 0000-0001-8022-196X ; 0000-0003-1903-270X ; 0000-0003-1076-3610</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,4009,27902,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28959811$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-02176719$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Kato, Atsushi</creatorcontrib><creatorcontrib>Nakagome, Izumi</creatorcontrib><creatorcontrib>Nakagawa, Shinpei</creatorcontrib><creatorcontrib>Kinami, Kyoko</creatorcontrib><creatorcontrib>Adachi, Isao</creatorcontrib><creatorcontrib>Jenkinson, Sarah F</creatorcontrib><creatorcontrib>Désiré, Jérôme</creatorcontrib><creatorcontrib>Blériot, Yves</creatorcontrib><creatorcontrib>Nash, Robert J</creatorcontrib><creatorcontrib>Fleet, George W J</creatorcontrib><creatorcontrib>Hirono, Shuichi</creatorcontrib><title>In silico analyses of essential interactions of iminosugars with the Hex A active site and evaluation of their pharmacological chaperone effects for Tay-Sachs disease</title><title>Organic & biomolecular chemistry</title><addtitle>Org Biomol Chem</addtitle><description>The affinity of a series of iminosugar-based inhibitors exhibiting various ring sizes toward Hex A and their essential interactions with the enzyme active site were investigated. All the Hex A-inhibiting iminosugars tested formed hydrogen bonds with Arg178, Asp322, Tyr421 and Glu462 and had the favorable cation-π interaction with Trp460. Among them, DMDP amide (6) proved to be the most potent competitive inhibitor with a K
value of 0.041 μM. We analyzed the dynamic properties of both DMDP amide (6) and DNJNAc (1) in aqueous solution using molecular dynamics (MD) calculations; the distance of the interaction between Asp322 and 3-OH and Glu323 and 6-OH was important for stable interactions with Hex A, reducing fluctuations in the plasticity of the active site. DMDP amide (6) dose-dependently increased intracellular Hex A activity in the G269S mutant cells and restored Hex A activity up to approximately 43% of the wild type level; this effect clearly exceeded the border line treatment for Tay-Sachs disease, which is regarded as 10-15% of the wild type level. This is a significantly greater effect than that of pyrimethamine, which is currently in Phase 2 clinical trials. DMDP amide (6), therefore, represents a new promising pharmacological chaperone candidate for the treatment of Tay-Sachs disease.</description><subject>Catalysis</subject><subject>Catalytic Domain</subject><subject>Chemical bonds</subject><subject>Chemical Sciences</subject><subject>Clinical trials</subject><subject>Computer Simulation</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Hexosaminidase A - antagonists & inhibitors</subject><subject>Hexosaminidase A - chemistry</subject><subject>Hexosaminidase A - genetics</subject><subject>Hexosaminidase A - metabolism</subject><subject>Humans</subject><subject>Hydrogen bonding</subject><subject>Hydrogen bonds</subject><subject>Medical research</subject><subject>Medical treatment</subject><subject>Molecular dynamics</subject><subject>Molecular Dynamics Simulation</subject><subject>Mutation</subject><subject>Pharmacology</subject><subject>Pyrimethamine</subject><subject>Sugars - chemistry</subject><subject>Sugars - metabolism</subject><subject>Sugars - pharmacology</subject><subject>Sugars - therapeutic use</subject><subject>Tay-Sachs disease</subject><subject>Tay-Sachs Disease - drug therapy</subject><subject>Variation</subject><issn>1477-0520</issn><issn>1477-0539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc-O0zAQhyMEYpfChQdAlrgAUsB_Y_tYKpauVGkPLOdo6k42XiVxsZMufSGeE2e79MBpRuNvPo38K4q3jH5mVNgvToct5dyw5llxyaTWJVXCPj_3nF4Ur1K6p5RZXcmXxQU3VlnD2GXx53ogyXfeBQIDdMeEiYSGYEo4jB464ocRI7jRh-Hxxfd-CGm6g5jIgx9bMrZI1vibLMlMHTDrRsyyHcEDdBPMm_Ni5nwk-xZiDy504c67rHct7DGGAQk2DboxkSZEcgvH8ge4NpGdTwgJXxcvGugSvnmqi-Ln1bfb1brc3Hy_Xi03pRPSjmXFUQhrKqb4zrpKU2e0pELIXLWRvJHWGIsaGTDkaiucBK6U4qCcktSIRfHx5G2hq_fR9xCPdQBfr5ebep5RznSlmT2wzH44sfsYfk2Yxrr3yWHXwYBhSjWzUs20FBl9_x96H6aY_zvVnDJqtBU5skXx6US5GFKK2JwvYLSek65X-ubrY9JXGX73pJy2Pe7O6L9oxV__naN8</recordid><startdate>2017</startdate><enddate>2017</enddate><creator>Kato, Atsushi</creator><creator>Nakagome, Izumi</creator><creator>Nakagawa, Shinpei</creator><creator>Kinami, Kyoko</creator><creator>Adachi, Isao</creator><creator>Jenkinson, Sarah F</creator><creator>Désiré, Jérôme</creator><creator>Blériot, Yves</creator><creator>Nash, Robert J</creator><creator>Fleet, George W J</creator><creator>Hirono, Shuichi</creator><general>Royal Society of Chemistry</general><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>7QO</scope><scope>7T7</scope><scope>7TM</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-3209-9282</orcidid><orcidid>https://orcid.org/0000-0001-8022-196X</orcidid><orcidid>https://orcid.org/0000-0003-1903-270X</orcidid><orcidid>https://orcid.org/0000-0003-1076-3610</orcidid></search><sort><creationdate>2017</creationdate><title>In silico analyses of essential interactions of iminosugars with the Hex A active site and evaluation of their pharmacological chaperone effects for Tay-Sachs disease</title><author>Kato, Atsushi ; Nakagome, Izumi ; Nakagawa, Shinpei ; Kinami, Kyoko ; Adachi, Isao ; Jenkinson, Sarah F ; Désiré, Jérôme ; Blériot, Yves ; Nash, Robert J ; Fleet, George W J ; Hirono, Shuichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c349t-62e33986152d9c670c8740334c877842f49889e7e1a1e25b3c4a25552a5c54083</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Catalysis</topic><topic>Catalytic Domain</topic><topic>Chemical bonds</topic><topic>Chemical Sciences</topic><topic>Clinical trials</topic><topic>Computer Simulation</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzyme Inhibitors - therapeutic use</topic><topic>Hexosaminidase A - antagonists & inhibitors</topic><topic>Hexosaminidase A - chemistry</topic><topic>Hexosaminidase A - genetics</topic><topic>Hexosaminidase A - metabolism</topic><topic>Humans</topic><topic>Hydrogen bonding</topic><topic>Hydrogen bonds</topic><topic>Medical research</topic><topic>Medical treatment</topic><topic>Molecular dynamics</topic><topic>Molecular Dynamics Simulation</topic><topic>Mutation</topic><topic>Pharmacology</topic><topic>Pyrimethamine</topic><topic>Sugars - chemistry</topic><topic>Sugars - metabolism</topic><topic>Sugars - pharmacology</topic><topic>Sugars - therapeutic use</topic><topic>Tay-Sachs disease</topic><topic>Tay-Sachs Disease - drug therapy</topic><topic>Variation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kato, Atsushi</creatorcontrib><creatorcontrib>Nakagome, Izumi</creatorcontrib><creatorcontrib>Nakagawa, Shinpei</creatorcontrib><creatorcontrib>Kinami, Kyoko</creatorcontrib><creatorcontrib>Adachi, Isao</creatorcontrib><creatorcontrib>Jenkinson, Sarah F</creatorcontrib><creatorcontrib>Désiré, Jérôme</creatorcontrib><creatorcontrib>Blériot, Yves</creatorcontrib><creatorcontrib>Nash, Robert J</creatorcontrib><creatorcontrib>Fleet, George W J</creatorcontrib><creatorcontrib>Hirono, Shuichi</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Organic & biomolecular chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kato, Atsushi</au><au>Nakagome, Izumi</au><au>Nakagawa, Shinpei</au><au>Kinami, Kyoko</au><au>Adachi, Isao</au><au>Jenkinson, Sarah F</au><au>Désiré, Jérôme</au><au>Blériot, Yves</au><au>Nash, Robert J</au><au>Fleet, George W J</au><au>Hirono, Shuichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In silico analyses of essential interactions of iminosugars with the Hex A active site and evaluation of their pharmacological chaperone effects for Tay-Sachs disease</atitle><jtitle>Organic & biomolecular chemistry</jtitle><addtitle>Org Biomol Chem</addtitle><date>2017</date><risdate>2017</risdate><volume>15</volume><issue>44</issue><spage>9297</spage><epage>9304</epage><pages>9297-9304</pages><issn>1477-0520</issn><eissn>1477-0539</eissn><abstract>The affinity of a series of iminosugar-based inhibitors exhibiting various ring sizes toward Hex A and their essential interactions with the enzyme active site were investigated. All the Hex A-inhibiting iminosugars tested formed hydrogen bonds with Arg178, Asp322, Tyr421 and Glu462 and had the favorable cation-π interaction with Trp460. Among them, DMDP amide (6) proved to be the most potent competitive inhibitor with a K
value of 0.041 μM. We analyzed the dynamic properties of both DMDP amide (6) and DNJNAc (1) in aqueous solution using molecular dynamics (MD) calculations; the distance of the interaction between Asp322 and 3-OH and Glu323 and 6-OH was important for stable interactions with Hex A, reducing fluctuations in the plasticity of the active site. DMDP amide (6) dose-dependently increased intracellular Hex A activity in the G269S mutant cells and restored Hex A activity up to approximately 43% of the wild type level; this effect clearly exceeded the border line treatment for Tay-Sachs disease, which is regarded as 10-15% of the wild type level. This is a significantly greater effect than that of pyrimethamine, which is currently in Phase 2 clinical trials. DMDP amide (6), therefore, represents a new promising pharmacological chaperone candidate for the treatment of Tay-Sachs disease.</abstract><cop>England</cop><pub>Royal Society of Chemistry</pub><pmid>28959811</pmid><doi>10.1039/c7ob02281f</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0002-3209-9282</orcidid><orcidid>https://orcid.org/0000-0001-8022-196X</orcidid><orcidid>https://orcid.org/0000-0003-1903-270X</orcidid><orcidid>https://orcid.org/0000-0003-1076-3610</orcidid></addata></record> |
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| subjects | Catalysis Catalytic Domain Chemical bonds Chemical Sciences Clinical trials Computer Simulation Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Hexosaminidase A - antagonists & inhibitors Hexosaminidase A - chemistry Hexosaminidase A - genetics Hexosaminidase A - metabolism Humans Hydrogen bonding Hydrogen bonds Medical research Medical treatment Molecular dynamics Molecular Dynamics Simulation Mutation Pharmacology Pyrimethamine Sugars - chemistry Sugars - metabolism Sugars - pharmacology Sugars - therapeutic use Tay-Sachs disease Tay-Sachs Disease - drug therapy Variation |
| title | In silico analyses of essential interactions of iminosugars with the Hex A active site and evaluation of their pharmacological chaperone effects for Tay-Sachs disease |
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