Abstract
IntroductionTwo recent models are in use for analysis of allosteric drug action at receptor sites remote from orthosteric binding sites. One is an allosteric two-state mechanical model derived in 2000 by David Hall. The other is an extended operational model developed in 2007 by Arthur Christopoulos’s group. The models are valid in pharmacology, enzymology, transportology as well as several other fields of biology involving allosteric concentration effects.ResultsI show here that Hall’s model for interactions between an orthoster, an alloster, and a receptive unit is the best choice of model both for simulation and analysis of allosteric concentration-responses at equilibrium or steady-state.ConclusionsAs detailed knowledge of receptors systems becomes available, systems with several pathways and states and/ or more than two binding sites should be analysed by extended forms of the Hall model rather than for instance a Hill type exponentiation of terms as introduced in non-mechanistic (operational) model approaches; yielding semi-quantitative estimates of actual system parameters based on Hill’s unlikely simultaneity model for G protein-coupled receptors.
Highlights
Two recent models are in use for analysis of allosteric drug action at receptor sites remote from orthosteric binding sites
I show here that Hall’s model for interactions between an orthoster, an alloster, and a receptive unit is the best choice of model both for simulation and analysis of allosteric concentration-responses at equilibrium or steady-state
Optimal allosteric models are in great demand, since mechanistic simulations may be combined with structural analysis of alloster binding, receptor multi-merization and association of molecules as G proteins, arrestins, and RAMPs into synthesis of Quantitative structure-activity-relationship (QSAR) for ligand binding and receptor activation [9,10,11,12,13,14,15,16]
Summary
As detailed knowledge of receptors systems becomes available, systems with several pathways and states and/ or more than two binding sites should be analysed by extended forms of the Hall model rather than for instance a Hill type exponentiation of terms as introduced in non-mechanistic (operational) model approaches; yielding semi-quantitative estimates of actual system parameters based on Hill’s unlikely simultaneity model for G protein-coupled receptors
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