A computational systems biology software platform for multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks.
A computational systems biology software platform for multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks.
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DOI：
10.3389/fphys.2011.00004
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发表时间：
2011
影响因子：
4
通讯作者：
Lippert J
中科院分区：
文献类型：
--
作者：
Eissing T;Kuepfer L;Becker C;Block M;Coboeken K;Gaub T;Goerlitz L;Jaeger J;Loosen R;Ludewig B;Meyer M;Niederalt C;Sevestre M;Siegmund HU;Solodenko J;Thelen K;Telle U;Weiss W;Wendl T;Willmann S;Lippert J
如今，计算机模拟研究和试验模拟已经补充了制药研发的实验方法，并已成为决策和与监管机构沟通的不可或缺的工具。虽然生物学本质上是多尺度的，但项目工作和软件工具通常集中在药物作用的孤立方面，例如生物体尺度上的药代动力学或分子水平上的药效学相互作用。我们提出了一个建模和仿真软件平台，由PK-Sim®和MoBi®组成，能够构建和仿真跨生物尺度集成的模型。构建胰腺肿瘤进展及其对药物治疗的反应的原型多尺度模型，并用通过肝代谢活化的前药治疗虚拟患者。肿瘤生长由导致细胞周期转换和增殖的信号转导驱动。活性代谢物的游离肿瘤浓度抑制信号级联中的Raf激酶，从而抑制细胞周期进展。在虚拟临床研究中，针对具有异质基因组背景的大群体模拟化疗干预的个体治疗结果。因此，该平台允许有效的模型构建和生物知识与来自所有生物尺度的先验数据的整合。实验性体外模型系统可以与动物实验和临床试验中的观察结果相联系。患者、疾病和药物之间的相互作用以及具有高度临床相关性的主题，例如药物基因组学、药物-药物或药物-代谢物相互作用的作用，可以使用这种机制、洞察力驱动的多尺度建模方法来解决。
Today, in silico studies and trial simulations already complement experimental approaches in pharmaceutical R&D and have become indispensable tools for decision making and communication with regulatory agencies. While biology is multiscale by nature, project work, and software tools usually focus on isolated aspects of drug action, such as pharmacokinetics at the organism scale or pharmacodynamic interaction on the molecular level. We present a modeling and simulation software platform consisting of PK-Sim® and MoBi® capable of building and simulating models that integrate across biological scales. A prototypical multiscale model for the progression of a pancreatic tumor and its response to pharmacotherapy is constructed and virtual patients are treated with a prodrug activated by hepatic metabolization. Tumor growth is driven by signal transduction leading to cell cycle transition and proliferation. Free tumor concentrations of the active metabolite inhibit Raf kinase in the signaling cascade and thereby cell cycle progression. In a virtual clinical study, the individual therapeutic outcome of the chemotherapeutic intervention is simulated for a large population with heterogeneous genomic background. Thereby, the platform allows efficient model building and integration of biological knowledge and prior data from all biological scales. Experimental in vitro model systems can be linked with observations in animal experiments and clinical trials. The interplay between patients, diseases, and drugs and topics with high clinical relevance such as the role of pharmacogenomics, drug–drug, or drug–metabolite interactions can be addressed using this mechanistic, insight driven multiscale modeling approach.
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影响因子：
16
作者：
Cohen-Saidon, Cellina;Cohen, Ariel A.;Alon, Uri
通讯作者：
Alon, Uri
影响因子：
5.8
作者：
Hucka, M;Finney, A;Wang, J
通讯作者：
Wang, J
影响因子：
4.5
作者：
Edginton, Andrea N.;Willmann, Stefan
通讯作者：
Willmann, Stefan
影响因子：
3.4
作者：
Brú, A;Albertos, S;Brú, I
通讯作者：
Brú, I
影响因子：
3.8
作者：
Berezhkovskiy, LM
通讯作者：
Berezhkovskiy, LM