Exploring the plasticity of the InhA substrate-binding site using new diaryl ether inhibitors
[Display omitted] •Design and synthesis of new diaryl ether derivatives that target InhA.•Bis-diaryl ethers with improved activity against the enzyme.•Crystal structure of InhA-NAD+ in complex with the most potent compound.•Structural analysis revealed the protein adaptability to relatively large in...
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| Veröffentlicht in: | Bioorganic chemistry 2024-02, Vol.143, p.107032-107032, Article 107032 |
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| creator | Tamhaev, Rasoul Grosjean, Emeline Ahamed, Hikmat Chebaiki, Mélina Rodriguez, Frédéric Recchia, Deborah Degiacomi, Giulia Pasca, Maria Rosalia Maveyraud, Laurent Mourey, Lionel Lherbet, Christian |
| description | [Display omitted]
•Design and synthesis of new diaryl ether derivatives that target InhA.•Bis-diaryl ethers with improved activity against the enzyme.•Crystal structure of InhA-NAD+ in complex with the most potent compound.•Structural analysis revealed the protein adaptability to relatively large inhibitors.•Opening of the minor portal underlines molecular plasticity.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a worldwide scourge with more than 10 million people affected yearly. Among the proteins essential for the survival of Mtb, InhA has been and is still clinically validated as a therapeutic target. A new family of direct diaryl ether inhibitors, not requiring prior activation by the catalase peroxidase enzyme KatG, has been designed with the ambition of fully occupying the InhA substrate-binding site. Thus, eleven compounds, featuring three pharmacophores within the same molecule, were synthesized. One of them, 5-(((4-(2-hydroxyphenoxy)benzyl)(octyl)amino)methyl)-2-phenoxyphenol (compound 21), showed good inhibitory activity against InhA with IC50 of 0.70 µM. The crystal structure of compound 21 in complex with InhA/NAD+ showed how the molecule fills the substrate-binding site as well as the minor portal of InhA. This study represents a further step towards the design of new inhibitors of InhA. |
| doi_str_mv | 10.1016/j.bioorg.2023.107032 |
| format | Article |
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•Design and synthesis of new diaryl ether derivatives that target InhA.•Bis-diaryl ethers with improved activity against the enzyme.•Crystal structure of InhA-NAD+ in complex with the most potent compound.•Structural analysis revealed the protein adaptability to relatively large inhibitors.•Opening of the minor portal underlines molecular plasticity.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a worldwide scourge with more than 10 million people affected yearly. Among the proteins essential for the survival of Mtb, InhA has been and is still clinically validated as a therapeutic target. A new family of direct diaryl ether inhibitors, not requiring prior activation by the catalase peroxidase enzyme KatG, has been designed with the ambition of fully occupying the InhA substrate-binding site. Thus, eleven compounds, featuring three pharmacophores within the same molecule, were synthesized. One of them, 5-(((4-(2-hydroxyphenoxy)benzyl)(octyl)amino)methyl)-2-phenoxyphenol (compound 21), showed good inhibitory activity against InhA with IC50 of 0.70 µM. The crystal structure of compound 21 in complex with InhA/NAD+ showed how the molecule fills the substrate-binding site as well as the minor portal of InhA. This study represents a further step towards the design of new inhibitors of InhA.</description><identifier>ISSN: 0045-2068</identifier><identifier>EISSN: 1090-2120</identifier><identifier>DOI: 10.1016/j.bioorg.2023.107032</identifier><identifier>PMID: 38128204</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Antitubercular Agents - chemistry ; Antitubercular Agents - pharmacology ; Bacterial Proteins - metabolism ; Bacteriology ; Binding Sites ; Chemical Sciences ; Cristallography ; Diaryl ethers ; Ether ; Ethers ; Ethyl Ethers ; Humans ; Imidazoles ; InhA ; Inhibitors ; Life Sciences ; Medicinal Chemistry ; Microbiology and Parasitology ; Minor portal ; Mycobacterium tuberculosis ; Sulfonamides ; Thiophenes ; Tuberculosis ; X-ray crystallography</subject><ispartof>Bioorganic chemistry, 2024-02, Vol.143, p.107032-107032, Article 107032</ispartof><rights>2023 Elsevier Inc.</rights><rights>Copyright © 2023 Elsevier Inc. All rights reserved.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-6980500fed3d258e57793533e2eb93092b1839942547dc5db1e0d9f51554e5a13</citedby><cites>FETCH-LOGICAL-c396t-6980500fed3d258e57793533e2eb93092b1839942547dc5db1e0d9f51554e5a13</cites><orcidid>0000-0002-8259-1259 ; 0000-0001-5427-5040 ; 0000-0001-5491-8165 ; 0000-0003-4610-8319</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bioorg.2023.107032$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38128204$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-04389877$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Tamhaev, Rasoul</creatorcontrib><creatorcontrib>Grosjean, Emeline</creatorcontrib><creatorcontrib>Ahamed, Hikmat</creatorcontrib><creatorcontrib>Chebaiki, Mélina</creatorcontrib><creatorcontrib>Rodriguez, Frédéric</creatorcontrib><creatorcontrib>Recchia, Deborah</creatorcontrib><creatorcontrib>Degiacomi, Giulia</creatorcontrib><creatorcontrib>Pasca, Maria Rosalia</creatorcontrib><creatorcontrib>Maveyraud, Laurent</creatorcontrib><creatorcontrib>Mourey, Lionel</creatorcontrib><creatorcontrib>Lherbet, Christian</creatorcontrib><title>Exploring the plasticity of the InhA substrate-binding site using new diaryl ether inhibitors</title><title>Bioorganic chemistry</title><addtitle>Bioorg Chem</addtitle><description>[Display omitted]
•Design and synthesis of new diaryl ether derivatives that target InhA.•Bis-diaryl ethers with improved activity against the enzyme.•Crystal structure of InhA-NAD+ in complex with the most potent compound.•Structural analysis revealed the protein adaptability to relatively large inhibitors.•Opening of the minor portal underlines molecular plasticity.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a worldwide scourge with more than 10 million people affected yearly. Among the proteins essential for the survival of Mtb, InhA has been and is still clinically validated as a therapeutic target. A new family of direct diaryl ether inhibitors, not requiring prior activation by the catalase peroxidase enzyme KatG, has been designed with the ambition of fully occupying the InhA substrate-binding site. Thus, eleven compounds, featuring three pharmacophores within the same molecule, were synthesized. One of them, 5-(((4-(2-hydroxyphenoxy)benzyl)(octyl)amino)methyl)-2-phenoxyphenol (compound 21), showed good inhibitory activity against InhA with IC50 of 0.70 µM. The crystal structure of compound 21 in complex with InhA/NAD+ showed how the molecule fills the substrate-binding site as well as the minor portal of InhA. This study represents a further step towards the design of new inhibitors of InhA.</description><subject>Antitubercular Agents - chemistry</subject><subject>Antitubercular Agents - pharmacology</subject><subject>Bacterial Proteins - metabolism</subject><subject>Bacteriology</subject><subject>Binding Sites</subject><subject>Chemical Sciences</subject><subject>Cristallography</subject><subject>Diaryl ethers</subject><subject>Ether</subject><subject>Ethers</subject><subject>Ethyl Ethers</subject><subject>Humans</subject><subject>Imidazoles</subject><subject>InhA</subject><subject>Inhibitors</subject><subject>Life Sciences</subject><subject>Medicinal Chemistry</subject><subject>Microbiology and Parasitology</subject><subject>Minor portal</subject><subject>Mycobacterium tuberculosis</subject><subject>Sulfonamides</subject><subject>Thiophenes</subject><subject>Tuberculosis</subject><subject>X-ray crystallography</subject><issn>0045-2068</issn><issn>1090-2120</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9v1DAQxS0EokvhGyCUIxyyjP8l9gVpVRVaaSUucERWEk-6s8rGi-0U-u1JSOmR04yefm9mNI-xtxy2HHj18bhtKYR4txUg5CzVIMUztuFgoRRcwHO2AVC6FFCZC_YqpSMA56quXrILabgwAtSG_bj-fR5CpPGuyAcszkOTMnWUH4rQ_1Vux8OuSFObcmwyli2NfoETZSymtLQj_io8NfFhKHB2xILGA7WUQ0yv2Yu-GRK-eayX7Pvn629XN-X-65fbq92-7KStcllZAxqgRy-90AZ1XVuppUSBrZVgRcuNtFYJrWrfad9yBG97zbVWqBsuL9mHde6hGdw50mm-xoWG3M1u7xYNlDTW1PX9wr5f2XMMPydM2Z0odTgMzYhhSk5Y0JorU8GMqhXtYkgpYv80m4NbQnBHt4bglhDcGsJse_e4YWpP6J9M_74-A59WAOef3BNGlzrCsUNPEbvsfKD_b_gDgIKYhw</recordid><startdate>20240201</startdate><enddate>20240201</enddate><creator>Tamhaev, Rasoul</creator><creator>Grosjean, Emeline</creator><creator>Ahamed, Hikmat</creator><creator>Chebaiki, Mélina</creator><creator>Rodriguez, Frédéric</creator><creator>Recchia, Deborah</creator><creator>Degiacomi, Giulia</creator><creator>Pasca, Maria Rosalia</creator><creator>Maveyraud, Laurent</creator><creator>Mourey, Lionel</creator><creator>Lherbet, Christian</creator><general>Elsevier Inc</general><general>Elsevier</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>7X8</scope><scope>1XC</scope><scope>VOOES</scope><orcidid>https://orcid.org/0000-0002-8259-1259</orcidid><orcidid>https://orcid.org/0000-0001-5427-5040</orcidid><orcidid>https://orcid.org/0000-0001-5491-8165</orcidid><orcidid>https://orcid.org/0000-0003-4610-8319</orcidid></search><sort><creationdate>20240201</creationdate><title>Exploring the plasticity of the InhA substrate-binding site using new diaryl ether inhibitors</title><author>Tamhaev, Rasoul ; Grosjean, Emeline ; Ahamed, Hikmat ; Chebaiki, Mélina ; Rodriguez, Frédéric ; Recchia, Deborah ; Degiacomi, Giulia ; Pasca, Maria Rosalia ; Maveyraud, Laurent ; Mourey, Lionel ; Lherbet, Christian</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-6980500fed3d258e57793533e2eb93092b1839942547dc5db1e0d9f51554e5a13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Antitubercular Agents - chemistry</topic><topic>Antitubercular Agents - pharmacology</topic><topic>Bacterial Proteins - metabolism</topic><topic>Bacteriology</topic><topic>Binding Sites</topic><topic>Chemical Sciences</topic><topic>Cristallography</topic><topic>Diaryl ethers</topic><topic>Ether</topic><topic>Ethers</topic><topic>Ethyl Ethers</topic><topic>Humans</topic><topic>Imidazoles</topic><topic>InhA</topic><topic>Inhibitors</topic><topic>Life Sciences</topic><topic>Medicinal Chemistry</topic><topic>Microbiology and Parasitology</topic><topic>Minor portal</topic><topic>Mycobacterium tuberculosis</topic><topic>Sulfonamides</topic><topic>Thiophenes</topic><topic>Tuberculosis</topic><topic>X-ray crystallography</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tamhaev, Rasoul</creatorcontrib><creatorcontrib>Grosjean, Emeline</creatorcontrib><creatorcontrib>Ahamed, Hikmat</creatorcontrib><creatorcontrib>Chebaiki, Mélina</creatorcontrib><creatorcontrib>Rodriguez, Frédéric</creatorcontrib><creatorcontrib>Recchia, Deborah</creatorcontrib><creatorcontrib>Degiacomi, Giulia</creatorcontrib><creatorcontrib>Pasca, Maria Rosalia</creatorcontrib><creatorcontrib>Maveyraud, Laurent</creatorcontrib><creatorcontrib>Mourey, Lionel</creatorcontrib><creatorcontrib>Lherbet, Christian</creatorcontrib><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><collection>Hyper Article en Ligne (HAL)</collection><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><jtitle>Bioorganic chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tamhaev, Rasoul</au><au>Grosjean, Emeline</au><au>Ahamed, Hikmat</au><au>Chebaiki, Mélina</au><au>Rodriguez, Frédéric</au><au>Recchia, Deborah</au><au>Degiacomi, Giulia</au><au>Pasca, Maria Rosalia</au><au>Maveyraud, Laurent</au><au>Mourey, Lionel</au><au>Lherbet, Christian</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Exploring the plasticity of the InhA substrate-binding site using new diaryl ether inhibitors</atitle><jtitle>Bioorganic chemistry</jtitle><addtitle>Bioorg Chem</addtitle><date>2024-02-01</date><risdate>2024</risdate><volume>143</volume><spage>107032</spage><epage>107032</epage><pages>107032-107032</pages><artnum>107032</artnum><issn>0045-2068</issn><eissn>1090-2120</eissn><abstract>[Display omitted]
•Design and synthesis of new diaryl ether derivatives that target InhA.•Bis-diaryl ethers with improved activity against the enzyme.•Crystal structure of InhA-NAD+ in complex with the most potent compound.•Structural analysis revealed the protein adaptability to relatively large inhibitors.•Opening of the minor portal underlines molecular plasticity.
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a worldwide scourge with more than 10 million people affected yearly. Among the proteins essential for the survival of Mtb, InhA has been and is still clinically validated as a therapeutic target. A new family of direct diaryl ether inhibitors, not requiring prior activation by the catalase peroxidase enzyme KatG, has been designed with the ambition of fully occupying the InhA substrate-binding site. Thus, eleven compounds, featuring three pharmacophores within the same molecule, were synthesized. One of them, 5-(((4-(2-hydroxyphenoxy)benzyl)(octyl)amino)methyl)-2-phenoxyphenol (compound 21), showed good inhibitory activity against InhA with IC50 of 0.70 µM. The crystal structure of compound 21 in complex with InhA/NAD+ showed how the molecule fills the substrate-binding site as well as the minor portal of InhA. This study represents a further step towards the design of new inhibitors of InhA.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>38128204</pmid><doi>10.1016/j.bioorg.2023.107032</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-8259-1259</orcidid><orcidid>https://orcid.org/0000-0001-5427-5040</orcidid><orcidid>https://orcid.org/0000-0001-5491-8165</orcidid><orcidid>https://orcid.org/0000-0003-4610-8319</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Antitubercular Agents - chemistry Antitubercular Agents - pharmacology Bacterial Proteins - metabolism Bacteriology Binding Sites Chemical Sciences Cristallography Diaryl ethers Ether Ethers Ethyl Ethers Humans Imidazoles InhA Inhibitors Life Sciences Medicinal Chemistry Microbiology and Parasitology Minor portal Mycobacterium tuberculosis Sulfonamides Thiophenes Tuberculosis X-ray crystallography |
| title | Exploring the plasticity of the InhA substrate-binding site using new diaryl ether inhibitors |
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