In Silico-Guided Rational Drug Design and Synthesis of Novel 4‑(Thiophen-2-yl)butanamides as Potent and Selective TRPV1 Agonists
We describe an in silico-guided rational drug design and the synthesis of the suggested ligands, aimed at improving the TRPV1-ligand binding properties and the potency of N-(4-hydroxy-3-methoxybenzyl)-4-(thiophen-2-yl) butanamide I, a previously identified TRPV1 agonist. The docking experiments foll...
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| Veröffentlicht in: | Journal of medicinal chemistry 2023-05, Vol.66 (10), p.6994-7015 |
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| creator | Romeo, Isabella Brizzi, Antonella Pessina, Federica Ambrosio, Francesca Alessandra Aiello, Francesca Belardo, Carmela Carullo, Gabriele Costa, Giosuè De Petrocellis, Luciano Frosini, Maria Luongo, Livio Maramai, Samuele Paolino, Marco Moriello, Aniello Schiano Mugnaini, Claudia Scorzelli, Francesco Maione, Sabatino Corelli, Federico Di Marzo, Vincenzo Alcaro, Stefano Artese, Anna |
| description | We describe an in silico-guided rational drug design and the synthesis of the suggested ligands, aimed at improving the TRPV1-ligand binding properties and the potency of N-(4-hydroxy-3-methoxybenzyl)-4-(thiophen-2-yl) butanamide I, a previously identified TRPV1 agonist. The docking experiments followed by molecular dynamics simulations and thermodynamic analysis led the drug design toward both the introduction of a lipophilic iodine and a flat pyridine/benzene at position 5 of the thiophene nucleus. Most of the synthesized compounds showed high TRPV1 efficacy and potency as well as selectivity. The molecular modeling analysis highlighted crucial hydrophobic interactions between Leu547 and the iodo-thiophene nucleus, as in amide 2a, or between Phe543 and the pyridinyl moiety, as in 3a. In the biological evaluation, both compounds showed protective properties against oxidative stress-induced ROS formation in human keratinocytes. Additionally, while 2a showed neuroprotective effects in both neurons and rat brain slices, 3a exhibited potent antinociceptive effect in vivo.. |
| doi_str_mv | 10.1021/acs.jmedchem.3c00447 |
| format | Article |
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The docking experiments followed by molecular dynamics simulations and thermodynamic analysis led the drug design toward both the introduction of a lipophilic iodine and a flat pyridine/benzene at position 5 of the thiophene nucleus. Most of the synthesized compounds showed high TRPV1 efficacy and potency as well as selectivity. The molecular modeling analysis highlighted crucial hydrophobic interactions between Leu547 and the iodo-thiophene nucleus, as in amide 2a, or between Phe543 and the pyridinyl moiety, as in 3a. In the biological evaluation, both compounds showed protective properties against oxidative stress-induced ROS formation in human keratinocytes. Additionally, while 2a showed neuroprotective effects in both neurons and rat brain slices, 3a exhibited potent antinociceptive effect in vivo..</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.3c00447</identifier><identifier>PMID: 37192374</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amides ; Animals ; Drug Design ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Oxidative Stress ; Rats ; Thiophenes - chemistry ; Thiophenes - pharmacology ; TRPV Cation Channels - agonists</subject><ispartof>Journal of medicinal chemistry, 2023-05, Vol.66 (10), p.6994-7015</ispartof><rights>2023 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-e90d03044404ff1c1978548edc9daefaa52d5dc5b88277f6c9fc1b17d38055ac3</citedby><cites>FETCH-LOGICAL-a348t-e90d03044404ff1c1978548edc9daefaa52d5dc5b88277f6c9fc1b17d38055ac3</cites><orcidid>0000-0002-0437-358X ; 0000-0001-6846-5582 ; 0000-0002-2310-9899 ; 0000-0002-5750-4504 ; 0000-0002-1490-3070 ; 0000-0001-7499-6961 ; 0000-0002-1619-3295 ; 0000-0003-0947-9479 ; 0000-0003-4874-2946 ; 0000-0002-5799-7863</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.3c00447$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00447$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37192374$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Romeo, Isabella</creatorcontrib><creatorcontrib>Brizzi, Antonella</creatorcontrib><creatorcontrib>Pessina, Federica</creatorcontrib><creatorcontrib>Ambrosio, Francesca Alessandra</creatorcontrib><creatorcontrib>Aiello, Francesca</creatorcontrib><creatorcontrib>Belardo, Carmela</creatorcontrib><creatorcontrib>Carullo, Gabriele</creatorcontrib><creatorcontrib>Costa, Giosuè</creatorcontrib><creatorcontrib>De Petrocellis, Luciano</creatorcontrib><creatorcontrib>Frosini, Maria</creatorcontrib><creatorcontrib>Luongo, Livio</creatorcontrib><creatorcontrib>Maramai, Samuele</creatorcontrib><creatorcontrib>Paolino, Marco</creatorcontrib><creatorcontrib>Moriello, Aniello Schiano</creatorcontrib><creatorcontrib>Mugnaini, Claudia</creatorcontrib><creatorcontrib>Scorzelli, Francesco</creatorcontrib><creatorcontrib>Maione, Sabatino</creatorcontrib><creatorcontrib>Corelli, Federico</creatorcontrib><creatorcontrib>Di Marzo, Vincenzo</creatorcontrib><creatorcontrib>Alcaro, Stefano</creatorcontrib><creatorcontrib>Artese, Anna</creatorcontrib><title>In Silico-Guided Rational Drug Design and Synthesis of Novel 4‑(Thiophen-2-yl)butanamides as Potent and Selective TRPV1 Agonists</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>We describe an in silico-guided rational drug design and the synthesis of the suggested ligands, aimed at improving the TRPV1-ligand binding properties and the potency of N-(4-hydroxy-3-methoxybenzyl)-4-(thiophen-2-yl) butanamide I, a previously identified TRPV1 agonist. The docking experiments followed by molecular dynamics simulations and thermodynamic analysis led the drug design toward both the introduction of a lipophilic iodine and a flat pyridine/benzene at position 5 of the thiophene nucleus. Most of the synthesized compounds showed high TRPV1 efficacy and potency as well as selectivity. The molecular modeling analysis highlighted crucial hydrophobic interactions between Leu547 and the iodo-thiophene nucleus, as in amide 2a, or between Phe543 and the pyridinyl moiety, as in 3a. In the biological evaluation, both compounds showed protective properties against oxidative stress-induced ROS formation in human keratinocytes. 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Med. Chem</addtitle><date>2023-05-25</date><risdate>2023</risdate><volume>66</volume><issue>10</issue><spage>6994</spage><epage>7015</epage><pages>6994-7015</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>We describe an in silico-guided rational drug design and the synthesis of the suggested ligands, aimed at improving the TRPV1-ligand binding properties and the potency of N-(4-hydroxy-3-methoxybenzyl)-4-(thiophen-2-yl) butanamide I, a previously identified TRPV1 agonist. The docking experiments followed by molecular dynamics simulations and thermodynamic analysis led the drug design toward both the introduction of a lipophilic iodine and a flat pyridine/benzene at position 5 of the thiophene nucleus. Most of the synthesized compounds showed high TRPV1 efficacy and potency as well as selectivity. The molecular modeling analysis highlighted crucial hydrophobic interactions between Leu547 and the iodo-thiophene nucleus, as in amide 2a, or between Phe543 and the pyridinyl moiety, as in 3a. In the biological evaluation, both compounds showed protective properties against oxidative stress-induced ROS formation in human keratinocytes. 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| ispartof | Journal of medicinal chemistry, 2023-05, Vol.66 (10), p.6994-7015 |
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| subjects | Amides Animals Drug Design Humans Molecular Docking Simulation Molecular Dynamics Simulation Oxidative Stress Rats Thiophenes - chemistry Thiophenes - pharmacology TRPV Cation Channels - agonists |
| title | In Silico-Guided Rational Drug Design and Synthesis of Novel 4‑(Thiophen-2-yl)butanamides as Potent and Selective TRPV1 Agonists |
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