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Gaddum Memorial Lecture 2014: receptors as an evolving concept: from switches to biased microprocessors.

ABSTRACT: This review is based on the JR Vane Medal Lecture presented at the BPS Winter Meeting in December 2014 by T. Kenakin. A recording of the lecture is included as supporting information and can also be viewed online here: https://www.youtube.com/watch?v=xrP81AQ8l-8. Pharmacological models used to describe drug agonism and antagonism have evolved over the past 20 years from a parsimonious model describing single active and inactive receptor states to models of multiconformational receptor systems modified by ligand conformational selection. These latter models describe the observed, presently underexploited, pharmacological mechanism of ligand-directed biased signalling. Biased signals can be quantified with transduction coefficients (??Log(?/KA) values), a scale grounded in the Black/Leff operational model; this enables the optimization of biased profiles through medicinal chemistry. The past decades have also brought the availability of new technologies to measure multiple functional effects mediated by seven transmembrane receptors. These have confirmed that drugs can have many efficacies, which may be collaterally linked, that is there is no linear sequence of activities required. In addition, new functional screening assays have introduced increasing numbers of allosteric ligands into drug discovery. These molecules are permissive (they do not necessarily preclude endogenous signalling in vivo); therefore, they may allow better fine tuning of pathological physiology. The permissive quality of allosteric ligands can also change the quality of endogenous signalling efficacy ('induced bias') as well as the quantity of signal; in this regard, indices related to ??Log(?/KA) values (namely ?Log(??) values) can be used to quantify these effects for optimization in the drug discovery process. All of these added scales of drug activity will, hopefully, allow better targeting of candidate molecules towards therapies.

SUBMITTER: Kenakin T

PROVIDER: S-EPMC4556465 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Gaddum Memorial Lecture 2014: receptors as an evolving concept: from switches to biased microprocessors.

Kenakin Terry T

British journal of pharmacology 20150721 17

This review is based on the JR Vane Medal Lecture presented at the BPS Winter Meeting in December 2014 by T. Kenakin. A recording of the lecture is included as supporting information and can also be viewed online here: https://www.youtube.com/watch?v=xrP81AQ8l-8. Pharmacological models used to describe drug agonism and antagonism have evolved over the past 20 years from a parsimonious model describing single active and inactive receptor states to models of multiconformational receptor systems mo ...[more]

PMID: 26075971

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Project description:PurposeTo evaluate the importance of nutritional supplements, dietary pattern, and genetic associations in age-related macular degeneration (AMD); and to discuss the technique of artificial intelligence/deep learning to potentially enhance research in detecting and classifying AMD.DesignRetrospective literature review.MethodsTo review the studies of both prospective and retrospective (post hoc) analyses of nutrition, genetic variants, and deep learning in AMD in both the Age-Related Eye Disease Study (AREDS) and AREDS2.ResultsIn addition to demonstrating the beneficial effects of the AREDS and AREDS2 supplements of antioxidant vitamins and zinc (plus copper) for reducing the risk of progression to late AMD, these 2 studies also confirmed the importance of high adherence to Mediterranean diet in reducing progression of AMD in persons with varying severity of disease. In persons with the protective genetic alleles of complement factor H (CFH), the Mediterranean diet had further beneficial effect. However, despite the genetic association with AMD progression, prediction models found genetic information added little to the high predictive value of baseline severity of AMD for disease progression. The technique of deep learning, an arm of artificial intelligence, using color fundus photographs from AREDS/AREDS2 was superior in some cases and noninferior in others to clinical human grading (retinal specialists) and to the gold standard of the certified reading center graders.ConclusionsCounseling individuals affected with AMD regarding the use of the AREDS2 supplements and the beneficial association of the Mediterranean diet is an important public health message. Although genetic testing is important in research, it is not recommended for prediction of disease or to guide therapies and/or dietary interventions in AMD. Techniques in deep learning hold great promise, but further prospective research is required to validate the use of this technique to provide improvement in accuracy and sensitivity/specificity in clinical research and medical management of patients with AMD.

Dataset Information

Gaddum Memorial Lecture 2014: receptors as an evolving concept: from switches to biased microprocessors.

Publications

Gaddum Memorial Lecture 2014: receptors as an evolving concept: from switches to biased microprocessors.

Similar Datasets

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