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理解药物靶点细胞信号转导中的噪声问题。

Understanding noise in cell signalling in the prospect of drug-targets.

机构信息

Complex Analysis Group, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad 121001, India.

Agricultural and Ecological Research Unit, Indian Statistical Institute, 203 B.T. Road, Kolkata 700108, India.

出版信息

J Theor Biol. 2022 Dec 21;555:111298. doi: 10.1016/j.jtbi.2022.111298. Epub 2022 Oct 3.

Abstract

The introduction of noise to signals can alter central regulatory switches of cellular processes leading to diseases. Noise is inherently present in the cellular signalling system and plays a decisive role in the input-output (I/O) relation. The current study aims to understand the noise tolerance of motif structures in the cell signalling processes. The vulnerability of a node to noise could be a significant factor in causing signalling error and need to be controlled. We developed stochastic differential equation (SDE) based mathematical models for different network motifs with two nodes and studied the association between motif structure and signal-noise relation. A two-dimensional parameter space analysis on motif sensitivity with noise and input signal variation was performed to classify and rank the motifs. Identifying sensitive motifs and their high druggability infers their significance in screening potential drug-target candidates. Finally, we proposed a theoretical framework to identify nodes from a network as potential drug targets. We applied this mathematical formalism to three cancer networks to identify drug-targets and validated them with existing databases.

摘要

噪声引入信号会改变细胞过程的中央调节开关,导致疾病。噪声在细胞信号系统中是固有存在的,并在输入-输出(I/O)关系中起决定性作用。本研究旨在了解细胞信号过程中基序结构的噪声容忍度。节点对噪声的脆弱性可能是导致信号错误的重要因素,需要加以控制。我们为具有两个节点的不同网络基序开发了基于随机微分方程(SDE)的数学模型,并研究了基序结构与信号噪声关系之间的联系。通过对基序敏感性的二维参数空间分析,进行了噪声和输入信号变化的分析,以对基序进行分类和排序。识别敏感基序及其高药物可及性推断出它们在筛选潜在药物靶标候选物方面的重要性。最后,我们提出了一个理论框架,用于从网络中识别节点作为潜在的药物靶标。我们将这种数学形式应用于三个癌症网络,以识别药物靶标,并与现有的数据库进行验证。

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