Staschen C M, Homer L D
Naval Medical Research Institute, Thermal Stress Division (53), Bethesda, Maryland 20889-5607, USA.
J Pharmacokinet Biopharm. 1996 Dec;24(6):589-609. doi: 10.1007/BF02353482.
A computer was used to simulate data from typical radioligand binding experiments with a 2-site competitive-allosteric model of a receptor. The 4 equilibrium parameters of this model cannot be estimated by fitting the model to equilibrium data. Data from simulations of association experiments give satisfactory estimates of the 9 competitive-allosteric model parameters. From the kinetic parameters, equilibrium constants may be calculated. Combining data from equilibrium simulations with data from association simulations provided estimates of the model parameters with smaller standard deviations. A further improvement in design was shown possible by including simulated experiments in which receptor was preincubated with inhibitor before adding ligand. This improvement was documented using Monte Carlo replications of parameter estimates using competing experimental designs. Replications also revealed certain biases in the parameter estimates and could provide a means of estimating those biases when parameter estimates are made using experimental rather than simulated data. Simulations offer a powerful tool in planning experiments designed to estimate kinetic parameters of a receptor system. This is especially true with complex systems that may require pooling data from different kinds of experiments in order to estimate the kinetic parameters.
使用计算机通过受体的双位点竞争 - 变构模型模拟典型放射性配体结合实验的数据。该模型的4个平衡参数无法通过将模型拟合到平衡数据来估计。结合实验的数据能够对9个竞争 - 变构模型参数给出令人满意的估计。根据动力学参数，可以计算平衡常数。将平衡模拟数据与结合模拟数据相结合，能够以更小的标准差对模型参数进行估计。通过纳入在添加配体之前先将受体与抑制剂预孵育的模拟实验，显示出设计上进一步改进的可能性。使用竞争实验设计对参数估计进行蒙特卡罗重复验证，记录了这种改进。重复验证还揭示了参数估计中的某些偏差，并且当使用实验而非模拟数据进行参数估计时，可为估计这些偏差提供一种方法。模拟为规划旨在估计受体系统动力学参数的实验提供了一个强大的工具。对于可能需要汇集来自不同类型实验的数据以估计动力学参数的复杂系统而言，尤其如此。
