Fitting Models to Biological Data Using Linear and Nonlinear Regression: A Practical Guide to Curve Fitting
FITTING DATA WITH NONLINEAR REGRESSION FITTING DATA WITH LINEAR REGRESSION MODELS HOW NONLINEAR REGRESSION WORKS CONFIDENCE INTERVALS OF THE PARAMETERS COMPARING MODELS HOW DOES A TREATMENT CHANGE…
G Protein-Coupled Receptor Allosterism and Complexing
It is proposed that the study of allosteric phenomena will become of progressively greater import to the drug discovery process due to the advent of newer and more sensitive GPCR screening technologies.
Activation and allosteric modulation of a muscarinic acetylcholine receptor
The structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the β2AR and rhodopsin.
Functional Selectivity and Classical Concepts of Quantitative Pharmacology
Besides the heuristically interesting nature of functional selectivity, there is a clear impact on drug discovery, because this mechanism raises the possibility of selecting or designing novel ligands that differentially activate only a subset of functions of a single receptor, thereby optimizing therapeutic action.
Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders
There have been tremendous advances in the discovery of novel ligands for GPCRs that act at allosteric sites to regulate receptor function that provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders.
A simple method for quantifying functional selectivity and agonist bias.
- T. Kenakin, C. Watson, Vanessa M Muniz-Medina, A. Christopoulos, Steven J. Novick
- BiologyACS Chemical Neuroscience
- 21 March 2012
A scale based on the Black and Leff operational model that contains the key elements required to describe 7TM agonism, namely, affinity for the receptor and efficacy in activating a particular signaling pathway, can statistically evaluate selective agonist effects in a manner that can theoretically inform structure-activity studies and/or drug candidate selection matrices.
Allosteric Modulation of the Cannabinoid CB1 Receptor
The data presented clearly demonstrate, for the first time, that the cannabinoid CB1 receptor contains an allosteric binding site that can be recognized by synthetic small molecule ligands.
Signalling bias in new drug discovery: detection, quantification and therapeutic impact
A viewpoint on which methods are appropriate for quantifying bias is provided, based on knowledge of how cellular and intracellular signalling proteins control the conformation of seven-transmembrane receptors.
Allosteric binding sites on cell-surface receptors: novel targets for drug discovery
- A. Christopoulos
- Biology, ChemistryNature reviews. Drug discovery
- 1 March 2002
Allosteric modulators could offer several advantages over orthosteric ligands, including greater selectivity and saturability of their effect.
Novel Receptor Partners and Function of Receptor Activity-modifying Proteins*
These findings identify a new functional consequence of RAMP-receptor interaction, suggesting that RAMPs play a more general role in modulating cell signaling through other GPCRs than is currently appreciated.