Computer-aided targeting of the PI3K/Akt/mTOR pathway: toxicity reduction and therapeutic opportunities.
Computer-aided targeting of the PI3K/Akt/mTOR pathway: toxicity reduction and therapeutic opportunities.
复制标题
计算机辅助靶向 PI3K/Akt/mTOR 通路：毒性降低和治疗机会。
DOI：
10.3390/ijms151018856
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发表时间：
2014-10-20
影响因子：
5.6
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Li T;Wang G
PI 3 K/Akt/mTOR通路在广泛的生物学功能中起重要作用，包括代谢、大分子合成、细胞生长、增殖和存活。然而，它的多功能性使其成为许多病原体的突出目标;并且该途径的相应失调通常导致并发症，如肿瘤发生，2型糖尿病和心血管疾病。分子靶向治疗，旨在调节失调的途径，具有很大的希望，控制这些疾病，虽然副作用可能是不可避免的，鉴于无处不在的细胞功能的途径。在这里，我们回顾了各种因素，发现调节PI 3 K/Akt/mTOR通路，包括基因突变，某些代谢产物，炎症因子，化学毒物，药物发现纠正的途径，以及病毒劫持的途径，为自己的合成目的。此外，PI 3 K/Akt/mTOR通路改变和相关发病机制的证据激发了对该通路的计算机辅助靶向以优化治疗策略的探索。在此，我们讨论了几种可能的选择，使用计算机辅助靶向，以减少分子靶向治疗的毒性，包括数学建模，以揭示系统水平的控制机制，并赋予低剂量的联合治疗，PP 2A作为治疗靶点的潜力，参数的制定，以确定哪些患者将最受益于特定的靶向治疗和分子动力学模拟和对接研究以发现同种型特异性或突变选择性的药物，从而避免不期望的广泛抑制。我们希望这篇综述能激发药物发现的新想法，并加深我们对靶向PI 3 K/Akt/mTOR通路的可治愈性和毒性的理解。
The PI3K/Akt/mTOR pathway plays an essential role in a wide range of biological functions, including metabolism, macromolecular synthesis, cell growth, proliferation and survival. Its versatility, however, makes it a conspicuous target of many pathogens; and the consequential deregulations of this pathway often lead to complications, such as tumorigenesis, type 2 diabetes and cardiovascular diseases. Molecular targeted therapy, aimed at modulating the deregulated pathway, holds great promise for controlling these diseases, though side effects may be inevitable, given the ubiquity of the pathway in cell functions. Here, we review a variety of factors found to modulate the PI3K/Akt/mTOR pathway, including gene mutations, certain metabolites, inflammatory factors, chemical toxicants, drugs found to rectify the pathway, as well as viruses that hijack the pathway for their own synthetic purposes. Furthermore, this evidence of PI3K/Akt/mTOR pathway alteration and related pathogenesis has inspired the exploration of computer-aided targeting of this pathway to optimize therapeutic strategies. Herein, we discuss several possible options, using computer-aided targeting, to reduce the toxicity of molecularly-targeted therapy, including mathematical modeling, to reveal system-level control mechanisms and to confer a low-dosage combination therapy, the potential of PP2A as a therapeutic target, the formulation of parameters to identify patients who would most benefit from specific targeted therapies and molecular dynamics simulations and docking studies to discover drugs that are isoform specific or mutation selective so as to avoid undesired broad inhibitions. We hope this review will stimulate novel ideas for pharmaceutical discovery and deepen our understanding of curability and toxicity by targeting the PI3K/Akt/mTOR pathway.
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影响因子：
3.8
作者：
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通讯作者：
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