Mechanistic analysis of the function of agonists and allosteric modulators: reconciling two‐state and operational models
Mechanistic analysis of the function of agonists and allosteric modulators: reconciling two‐state and operational models
复制标题
激动剂和变构调节剂功能的机制分析：协调两种状态和操作模型
DOI：
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发表时间：
2013
影响因子：
7.3
通讯作者：
J. Giraldo
中科院分区：
文献类型：
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作者：
David Roche;D. Gil;J. Giraldo
比较激动作用和变构作用的双态和操作模型，以确定和表征常见的药理学参数。为了解释受体依赖性基础反应，在操作模型中考虑了组成型受体活性。通过将两态模型作为活性受体的分数，将操作模型作为相对于系统最大效应的分数响应，发现参数之间存在一一对应关系，通过比较分析可以更好地理解复杂的变构相互作用。特别地，在变构作用的操作模型中包括组成型受体活性允许表征能够降低系统的基础响应的调节剂;即，具有负内在功效的变构调节剂。理论模拟和整体的模型模拟数据的拟合优度表明，它是可行的，将模型应用到实验数据，并构成一个步骤，在受体理论形式主义。
Two‐state and operational models of both agonism and allosterism are compared to identify and characterize common pharmacological parameters. To account for the receptor‐dependent basal response, constitutive receptor activity is considered in the operational models. By arranging two‐state models as the fraction of active receptors and operational models as the fractional response relative to the maximum effect of the system, a one‐by‐one correspondence between parameters is found. The comparative analysis allows a better understanding of complex allosteric interactions. In particular, the inclusion of constitutive receptor activity in the operational model of allosterism allows the characterization of modulators able to lower the basal response of the system; that is, allosteric modulators with negative intrinsic efficacy. Theoretical simulations and overall goodness of fit of the models to simulated data suggest that it is feasible to apply the models to experimental data and constitute one step forward in receptor theory formalism.
影响因子：
7.3
作者：
Melancon, Bruce J.;Hopkins, Corey R.;Wood, Michael R.;Emmitte, Kyle A.;Niswender, Colleen M.;Christopoulos, Arthur;Conn, P. Jeffrey;Lindsley, Craig W.
通讯作者：
Lindsley, Craig W.