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David Roche, Debora Gil, & Jesus Giraldo. (2013). "Multiple active receptor conformation, agonist efficacy and maximum effect of the system: the conformation-based operational model of agonism, " . Drug Discovery Today, 18(7-8), 365–371.
Abstract: The operational model of agonism assumes that the maximum effect a particular receptor system can achieve (the Em parameter) is fixed. Em estimates are above but close to the asymptotic maximum effects of endogenous agonists. The concept of Em is contradicted by superagonists and those positive allosteric modulators that significantly increase the maximum effect of endogenous agonists. An extension of the operational model is proposed that assumes that the Em parameter does not necessarily have a single value for a receptor system but has multiple values associated to multiple active receptor conformations. The model provides a mechanistic link between active receptor conformation and agonist efficacy, which can be useful for the analysis of agonist response under different receptor scenarios.
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David Roche, Debora Gil, & Jesus Giraldo. (2013). "Mechanistic analysis of the function of agonists and allosteric modulators: Reconciling two-state and operational models " . British Journal of Pharmacology, 169(6), 1189–202.
Abstract: 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.
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Debora Gil, David Roche, Agnes Borras, & Jesus Giraldo. (2015). "Terminating Evolutionary Algorithms at their Steady State " . Computational Optimization and Applications, 61(2), 489–515.
Abstract: Assessing the reliability of termination conditions for evolutionary algorithms (EAs) is of prime importance. An erroneous or weak stop criterion can negatively affect both the computational effort and the final result. We introduce a statistical framework for assessing whether a termination condition is able to stop an EA at its steady state, so that its results can not be improved anymore. We use a regression model in order to determine the requirements ensuring that a measure derived from EA evolving population is related to the distance to the optimum in decision variable space. Our framework is analyzed across 24 benchmark test functions and two standard termination criteria based on function fitness value in objective function space and EA population decision variable space distribution for the differential evolution (DE) paradigm. Results validate our framework as a powerful tool for determining the capability of a measure for terminating EA and the results also identify the decision variable space distribution as the best-suited for accurately terminating DE in real-world applications.
Keywords: Evolutionary algorithms; Termination condition; Steady state; Differential evolution
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