Kiril Kirilov , Maria Ponticelli , Toni Kühl , Harald Hübner , Maya G. Georgieva , Matthias Vogel , Aneliya A. Balacheva , Bodo Haas , Tamara I. Pajpanova , Maima Matin , Luigi Milella , Peter Gmeiner , Diana Imhof , Nikolay T. Tzvetkov
{"title":"靶向NTS1和NTS2受体的神经紧张素(8-13)类似物:体外和分子模型的比较研究","authors":"Kiril Kirilov , Maria Ponticelli , Toni Kühl , Harald Hübner , Maya G. Georgieva , Matthias Vogel , Aneliya A. Balacheva , Bodo Haas , Tamara I. Pajpanova , Maima Matin , Luigi Milella , Peter Gmeiner , Diana Imhof , Nikolay T. Tzvetkov","doi":"10.1016/j.crbiot.2025.100298","DOIUrl":null,"url":null,"abstract":"<div><div>The simultaneous activation of both neurotensin type 1 and 2 receptors (NTS1R and NTS2R) through the neuronal peptide neurotensin (NT), activating the dopamine (DA) release and DA signaling within the dopaminergic system in the brain, suggest that NTS1R/NTS2R dual-specific NT analogs may represent an attractive tool in the treatment of Parkinson’s disease (PD) and/or other related conditions. Herein, we report <em>in silico</em> exploration of NTS1R and NTS2R driven by <em>in vitro</em> pharmacological evaluation of the linear hexapeptide NT analogs <strong>3</strong> (sequence Lys<sup>8</sup>-Cav<sup>9</sup>-Pro<sup>10</sup>-Tyr<sup>11</sup>-Ile<sup>12</sup>-Leu<sup>13</sup>) and <strong>6</strong> (Arg<sup>8</sup>-Cav<sup>9</sup>-Pro<sup>10</sup>-Tyr<sup>11</sup>-Ile<sup>12</sup>-Leu<sup>13</sup>), both active towards the human NTS1R and NTS2R. Compared to the parent peptide NT(8–13) (<strong>2</strong>), compounds <strong>3</strong> and <strong>6</strong> showed improved <em>in vitro</em> human plasma stability and BBB permeability. Moreover, <em>in silico</em> ADMET evaluation indicated that both NT-analogs have strong pharmacological properties combined with good safety profiles, highlighting their potential for further structural improvements. Furthermore, we applied an AI-based approach to generate the homology models of hNTS1R and hNTS2R, followed by MD simulations of their ligand-free state and molecular docking in order to estimate the most probable protein–ligand complexes of peptides <strong>3</strong> and <strong>6</strong>. Binding interaction/affinity analysis of the best-ranked docking modes, obtained with selected time-frames from the respective MD trajectories, suggest that the receptor activation occurs via a ligand-receptor binding into the initial “entry” conformation of hNTS1R and hNTS2R. This assumption is supported by additional HYDE analysis confirming the binding affinities of peptides <strong>3</strong> and <strong>6</strong> towards hNTS1R and hNTS2R obtained by radioligand binding experiments. The reported study may serve as a ready-to-use <em>in silico</em> approach for further development of therapeutic options against PD and potentially other neurological disorders.</div></div>","PeriodicalId":52676,"journal":{"name":"Current Research in Biotechnology","volume":"9 ","pages":"Article 100298"},"PeriodicalIF":3.6000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Neurotensin(8-13) analogs targeting NTS1 and NTS2 receptors: A comparative in vitro and molecular modeling study\",\"authors\":\"Kiril Kirilov , Maria Ponticelli , Toni Kühl , Harald Hübner , Maya G. Georgieva , Matthias Vogel , Aneliya A. Balacheva , Bodo Haas , Tamara I. Pajpanova , Maima Matin , Luigi Milella , Peter Gmeiner , Diana Imhof , Nikolay T. Tzvetkov\",\"doi\":\"10.1016/j.crbiot.2025.100298\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>The simultaneous activation of both neurotensin type 1 and 2 receptors (NTS1R and NTS2R) through the neuronal peptide neurotensin (NT), activating the dopamine (DA) release and DA signaling within the dopaminergic system in the brain, suggest that NTS1R/NTS2R dual-specific NT analogs may represent an attractive tool in the treatment of Parkinson’s disease (PD) and/or other related conditions. Herein, we report <em>in silico</em> exploration of NTS1R and NTS2R driven by <em>in vitro</em> pharmacological evaluation of the linear hexapeptide NT analogs <strong>3</strong> (sequence Lys<sup>8</sup>-Cav<sup>9</sup>-Pro<sup>10</sup>-Tyr<sup>11</sup>-Ile<sup>12</sup>-Leu<sup>13</sup>) and <strong>6</strong> (Arg<sup>8</sup>-Cav<sup>9</sup>-Pro<sup>10</sup>-Tyr<sup>11</sup>-Ile<sup>12</sup>-Leu<sup>13</sup>), both active towards the human NTS1R and NTS2R. Compared to the parent peptide NT(8–13) (<strong>2</strong>), compounds <strong>3</strong> and <strong>6</strong> showed improved <em>in vitro</em> human plasma stability and BBB permeability. Moreover, <em>in silico</em> ADMET evaluation indicated that both NT-analogs have strong pharmacological properties combined with good safety profiles, highlighting their potential for further structural improvements. Furthermore, we applied an AI-based approach to generate the homology models of hNTS1R and hNTS2R, followed by MD simulations of their ligand-free state and molecular docking in order to estimate the most probable protein–ligand complexes of peptides <strong>3</strong> and <strong>6</strong>. Binding interaction/affinity analysis of the best-ranked docking modes, obtained with selected time-frames from the respective MD trajectories, suggest that the receptor activation occurs via a ligand-receptor binding into the initial “entry” conformation of hNTS1R and hNTS2R. This assumption is supported by additional HYDE analysis confirming the binding affinities of peptides <strong>3</strong> and <strong>6</strong> towards hNTS1R and hNTS2R obtained by radioligand binding experiments. The reported study may serve as a ready-to-use <em>in silico</em> approach for further development of therapeutic options against PD and potentially other neurological disorders.</div></div>\",\"PeriodicalId\":52676,\"journal\":{\"name\":\"Current Research in Biotechnology\",\"volume\":\"9 \",\"pages\":\"Article 100298\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2025-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current Research in Biotechnology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2590262825000292\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current Research in Biotechnology","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2590262825000292","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
Neurotensin(8-13) analogs targeting NTS1 and NTS2 receptors: A comparative in vitro and molecular modeling study
The simultaneous activation of both neurotensin type 1 and 2 receptors (NTS1R and NTS2R) through the neuronal peptide neurotensin (NT), activating the dopamine (DA) release and DA signaling within the dopaminergic system in the brain, suggest that NTS1R/NTS2R dual-specific NT analogs may represent an attractive tool in the treatment of Parkinson’s disease (PD) and/or other related conditions. Herein, we report in silico exploration of NTS1R and NTS2R driven by in vitro pharmacological evaluation of the linear hexapeptide NT analogs 3 (sequence Lys8-Cav9-Pro10-Tyr11-Ile12-Leu13) and 6 (Arg8-Cav9-Pro10-Tyr11-Ile12-Leu13), both active towards the human NTS1R and NTS2R. Compared to the parent peptide NT(8–13) (2), compounds 3 and 6 showed improved in vitro human plasma stability and BBB permeability. Moreover, in silico ADMET evaluation indicated that both NT-analogs have strong pharmacological properties combined with good safety profiles, highlighting their potential for further structural improvements. Furthermore, we applied an AI-based approach to generate the homology models of hNTS1R and hNTS2R, followed by MD simulations of their ligand-free state and molecular docking in order to estimate the most probable protein–ligand complexes of peptides 3 and 6. Binding interaction/affinity analysis of the best-ranked docking modes, obtained with selected time-frames from the respective MD trajectories, suggest that the receptor activation occurs via a ligand-receptor binding into the initial “entry” conformation of hNTS1R and hNTS2R. This assumption is supported by additional HYDE analysis confirming the binding affinities of peptides 3 and 6 towards hNTS1R and hNTS2R obtained by radioligand binding experiments. The reported study may serve as a ready-to-use in silico approach for further development of therapeutic options against PD and potentially other neurological disorders.
期刊介绍:
Current Research in Biotechnology (CRBIOT) is a new primary research, gold open access journal from Elsevier. CRBIOT publishes original papers, reviews, and short communications (including viewpoints and perspectives) resulting from research in biotechnology and biotech-associated disciplines.
Current Research in Biotechnology is a peer-reviewed gold open access (OA) journal and upon acceptance all articles are permanently and freely available. It is a companion to the highly regarded review journal Current Opinion in Biotechnology (2018 CiteScore 8.450) and is part of the Current Opinion and Research (CO+RE) suite of journals. All CO+RE journals leverage the Current Opinion legacy-of editorial excellence, high-impact, and global reach-to ensure they are a widely read resource that is integral to scientists' workflow.