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

IF 3.6 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
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
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引用次数: 0

摘要

通过神经元肽神经紧张素(NT)同时激活神经紧张素1型和2型受体(NTS1R和NTS2R),激活多巴胺(DA)释放和大脑多巴胺能系统内的DA信号,表明NTS1R/NTS2R双特异性NT类似物可能是治疗帕金森病(PD)和/或其他相关疾病的有吸引力的工具。本文通过对线状六肽NT类似物3(序列Lys8-Cav9-Pro10-Tyr11-Ile12-Leu13)和6(序列Arg8-Cav9-Pro10-Tyr11-Ile12-Leu13)的体外药理学评价,对NTS1R和NTS2R进行了芯片探索,这两个类似物都对人类NTS1R和NTS2R有活性。与母体肽NT(8-13)(2)相比,化合物3和6显示出体外人血浆稳定性和血脑屏障通透性的改善。此外,计算机ADMET评估表明,这两种nt -类似物具有强大的药理特性和良好的安全性,突出了它们进一步结构改进的潜力。此外,我们应用基于人工智能的方法生成hNTS1R和hNTS2R的同源性模型,然后对它们的无配体状态和分子对接进行MD模拟,以估计肽3和肽6最可能的蛋白质-配体复合物。结合相互作用/亲和分析的最佳对接模式,从各自的MD轨迹中选择的时间框架中获得,表明受体激活是通过配体-受体结合到hNTS1R和hNTS2R的初始“进入”构象中发生的。另外的HYDE分析证实了肽3和6对hNTS1R和hNTS2R的结合亲和力,这一假设得到了支持。该报告的研究可以作为一种现成的计算机方法,用于进一步开发针对PD和潜在的其他神经系统疾病的治疗选择。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.
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来源期刊
Current Research in Biotechnology
Current Research in Biotechnology Biochemistry, Genetics and Molecular Biology-Biotechnology
CiteScore
6.70
自引率
3.60%
发文量
50
审稿时长
38 days
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.
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