Neurotensin(8-13) analogs targeting NTS1 and NTS2 receptors: A comparative in vitro and molecular modeling study
Kirilov K, Ponticelli M, Kühl T, Hübner H, Georgieva MG, Vogel M, Balacheva AA, Haas B, Pajpanova TI, Matin M, Milella L, Gmeiner P, Imhof D, Tzvetkov NT (2025)
Publication Type: Journal article
Publication year: 2025
Book Volume: 9
Article Number: 100298
DOI: 10.1016/j.crbiot.2025.100298
Abstract
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.
Authors with CRIS profile
Harald Hübner
Lehrstuhl für Pharmazeutische Chemie
Peter Gmeiner
Lehrstuhl für Pharmazeutische Chemie
Additional Organisation(s)
Involved external institutions
Institute of Molecular Biology (IMB) / Institute of Molecular Biology Roumen Tsanev / Институт по молекулярна биология
Bulgaria (BG)
Rheinische Friedrich-Wilhelms-Universität Bonn
Germany (DE)
Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) / Federal Institute for Drugs and Medical Devices
Germany (DE)
Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences (IGHZ)
Poland (PL)
Università degli Studi della Basilicata
Italy (IT)
Bulgaria (BG)
Rheinische Friedrich-Wilhelms-Universität Bonn
Germany (DE)
Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) / Federal Institute for Drugs and Medical Devices
Germany (DE)
Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences (IGHZ)
Poland (PL)
Università degli Studi della Basilicata
Italy (IT)
How to cite
APA:
Kirilov, K., Ponticelli, M., Kühl, T., Hübner, H., Georgieva, M.G., Vogel, M.,... Tzvetkov, N.T. (2025). Neurotensin(8-13) analogs targeting NTS1 and NTS2 receptors: A comparative in vitro and molecular modeling study. , 9. https://doi.org/10.1016/j.crbiot.2025.100298
MLA:
Kirilov, Kiril, et al. "Neurotensin(8-13) analogs targeting NTS1 and NTS2 receptors: A comparative in vitro and molecular modeling study." 9 (2025).
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