Quantitative analysis of receptor allosterism and its implication for drug discovery.
BACKGROUND
G protein-coupled receptors represent the largest class of druggable targets and are known to be modulated by both orthosteric agonists and positive/negative allosteric modulators (PAMs/NAMs). Proper experimental design and data analysis for the dose matrix between an agonist and PAM or NAM are critical to elucidate the key parameters for understanding molecular mechanism and structure-activity relationship (SAR) in drug discovery.


METHODS
The authors provide an overview and best practice recommendations on the quantitative analysis of receptor allosterism. The authors propose a simple classification system for receptor modulators on the basis of their efficacy and affinity modifiers. The authors also outline the optimal assay designs for both fixed dose screening and dose matrix study of receptor modulators.


CONCLUSIONS
The authors recommend the global curve fitting approach to reliably yield system- and modulator-specific parameters for SAR ranking. Furthermore, the authors suggest that the uncertainty in maximal system response has insignificant impact on SAR ranking. The authors anticipate that systems pharmacology models integrating both binding kinetics and functional allosterism will be needed to address the inherent limitations of current allosterism models.
Merck Research Laboratories, Department of In Vitro Pharmacology , 2015 Galloping Hill Road, Kenilworth, NJ 07033 , USA rumin.zhang@merck.com.
Rumin
R
Zhang
Michael
M
Kavana
D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008954:Models, Biological; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D043562:Receptors, G-Protein-Coupled
G protein-couple receptor; Monte Carlo simulation; agonism; allosteric two-state model; bitopic or dualsteric agonist; full agonist; global curve fitting; negative allosteric modulators; operational model; orthosterism; partial agonist; positive allosteric modulator; receptor allosterism; silent allosteric modulator; β supremacy