摘要
背景:MAS激活的保护作用激发了开发MAS激动剂的临床兴趣。然而,目前推动该过程的基础排除了生理浓度的肽MAS激动剂诱导不能达到组成性激活的代谢功效的非典型信号传导。 MAS偶联的G蛋白的典型活化仅通过肽MAS-激动剂的超生理学浓度或化学修饰的类似物的生理浓度来实现。这些多效性差异是由于两个重叠的结合域:一个识别肽激动剂的非代谢型位点和一个识别修饰的类似物的代谢型域。 目标:超生理浓度的肽MAS激动剂进行结合代谢型结构域所需的化学修饰是可行的。受体寡聚化增强了与代谢型信号转导相关的药理学参数。受体 - 信号复合体复合物的形成使得激动剂的转导更具适应性。考虑到最近对MAS-信号体的鉴定,我们的目的是推测反向诱导拟合假说,其中MAS-信号体将触发激动剂结合MAS代谢结构域所需的化学修饰。 方法:本文从反向诱导拟合假说的角度,介绍了开发新型代谢型MAS激动剂的理性观点。 结果:预测MAS代谢型域的3D模型可指导代谢功效所需的化学修饰的筛选。基于药效团的虚拟筛选将从人类蛋白质组的虚拟文库中选择潜在的代谢型MAS激动剂。 结论:在开发MAS代谢型MAS激动剂时,考虑反应诱导拟合假说的理性观点代表了在生理浓度下提供具有组成型效力的MAS配体的最佳方法
关键词: MAS受体,MAS信号复合体,逆向诱导拟合,典型信号传导,配体结合域,分子模拟,代谢型激动剂,G蛋白偶联受体。
Current Medicinal Chemistry
Title:Reverse Induced Fit-Driven MAS-Downstream Transduction: Looking for Metabotropic Agonists
Volume: 24 Issue: 39
关键词: MAS受体,MAS信号复合体,逆向诱导拟合,典型信号传导,配体结合域,分子模拟,代谢型激动剂,G蛋白偶联受体。
摘要: Background: Protective effects of MAS activation have spurred clinical interests in developing MAS agonists. However, current bases that drive this process preclude that physiological concentrations of peptide MAS agonists induce an atypical signaling that does not reach the metabotropic efficacy of constitutive activation. Canonical activation of MAS-coupled G proteins is only achieved by supraphysiological concentrations of peptide MAS agonists or physiological concentrations of chemically modified analogues. These pleiotropic differences are because of two overlapped binding domains: one non-metabotropic site that recognizes peptide agonists and one metabotropic domain that recognizes modified analogues.
Objective: It is feasible that supraphysiological concentrations of peptide MAS agonists undergo to chemical modifications required for binding to metabotropic domain. Receptor oligomerization enhances pharmacological parameters coupled to metabotropic signaling. The formation of receptor-signalosome complex makes the transduction of agonists more adaptive. Considering the recent identification of MAS-signalosome, we aimed to postulate the reverse induced fit hypothesis in which MAS-signalosome would trigger chemical modifications required for agonists bind to MAS metabotropic domain.
Methods: Here we cover rational perspectives for developing novel metabotropic MAS agonists in the view of the reverse induced-fit hypothesis.
Results: Predicting a 3D model of MAS metabotropic domain may guide the screening of chemical modifications required for metabotropic efficacy. Pharmacophore-based virtual screening would select potential metabotropic MAS agonists from virtual libraries from human proteome.
Conclusions: Rational perspectives that consider reverse induced fit hypothesis during MAS activation for developing metabotropic MAS agonists represents the best approach in providing MAS ligands with constitutive efficacy at physiological concentrations.
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Cite this article as:
Reverse Induced Fit-Driven MAS-Downstream Transduction: Looking for Metabotropic Agonists, Current Medicinal Chemistry 2017; 24 (39) . https://dx.doi.org/10.2174/0929867324666170912095306
DOI https://dx.doi.org/10.2174/0929867324666170912095306 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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