Abstract
One of the goals of molecular pharmacology is to understand the machinery that converts information about the presence of a chemical (binding) to a functional consequence. Agonists are drugs which bind to their molecular targets and cause conformational changes underlying activation of the target. Inevitably, therefore, it can be difficult to disentangle the affinity of the agonist for the target from its efficacy in producing the ensuing conformational change. Efficacy depends on two factors: the intrinsic equilibrium between active and inactive states in the absence of agonist, and the energy contributed by the agonist due to the relative affinities of agonist for the active and inactive states. These difficulties are particularly frustrating when the goal is to determine the role(s) that particular residues in a target protein have in shaping the overall efficacy of a drug: how is it possible to unambiguously distinguish a role in determining intrinsic efficacy from one in determining relative affinity? This perspective highlights a research article in this issue (p.___) which demonstrates a quantitative approach to the resolution of this problem in the case of activation of the muscle nicotinic receptor. This elegant (if demanding) approach involves determining, separately, the consequences of specific mutations on gating in the unliganded and liganded states.
- Nicotinic cholinergic
- Structure-activity relationships and modeling
- Thermodynamic and kinetic processes and modeling
- Mutagenesis/Chimeric approaches
- Received November 22, 2010.
- Revision received December 17, 2010.
- Accepted December 20, 2010.
- The American Society for Pharmacology and Experimental Therapeutics