A Generalized Model and High Throughput Data Analysis System for Functional Modulation of Receptor-Agonist Systems Suitable for use in Drug Discovery
2013
Positive allosteric modulators (PAMs) of receptors represent a class of pharmacologic agents having the
desirable property of acting only in the presence of cognate ligands. Discovery and optimization of the structure activity
relationships of PAMs is complicated by the requirement of a second ligand to manifest their action, and by the need to
quantify both affinity and intrinsic efficacy. Multivariate regression analysis is a statistical method capable of
simultaneously obtaining affinity and intrinsic efficacy parameters from curve fits of multiple agonist dose-response
functions generated in the presence of varying concentrations of PAMs. Capitalizing on the advantages of multivariate
regression analysis for PAM optimization requires a theoretical framework and a system that facilitates efficient flow of
information from data generation through data analysis, storage, and retrieval. We describe here the experimental design,
mathematical model and informatics workflow enabling a multivariate regression approach for rapidly obtaining affinity
and intrinsic efficacy values for PAMs in a drug discovery setting.
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