Nuclear Receptors as Drug Targets

Abstract The biannual European Molecular Biology Organization (EMBO) conference on nuclear receptors was organized by Beatrice Desvergne and Laszlo Nagy and took place in Cavtat near Dubrovnik on the Adriatic coast of Croatia September 25–29, 2009. The meeting brought together researchers from all over the world covering a wide spectrum from fundamental mechanistic studies to metabolism, clinical studies, and drug development. In this report, we summarize the recent and exciting findings presented by the speakers at the meeting.

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Minireview: Genomics Versus Orphan Nuclear Receptors—A Half-Time Report

Molecular Endocrinology ◽

10.1210/mend.16.6.0849 ◽

2002 ◽

Vol 16 (6) ◽

pp. 1135-1144

Author(s):

Timothy M. Willson ◽

John T. Moore

Keyword(s):

Nuclear Receptors ◽

Drug Targets ◽

Hormone Receptors ◽

Receptor Gene ◽

Orphan Nuclear Receptors ◽

Orphan Receptors ◽

Genomic Technologies ◽

Full Complement ◽

And Function ◽

The Impact

Abstract Following the successful cloning of the orphan nuclear receptors during the 1990s we entered the 21st century with knowledge of the full complement of human nuclear receptors. Many of these proteins are ligand-activated transcription factors that act as the cognate receptors for steroid, retinoid, and thyroid hormones. In addition to these well characterized endocrine hormone receptors, there are a large number of orphan receptors of which less is known about the nature and function of their ligands. The task of deciphering the physiological function of these orphan receptors has been aided by a new generation of genomic technologies. Through application of chemical, structural, and functional genomics, several orphan nuclear receptors have emerged as pharmaceutical drug targets for the treatment of important human diseases. The significant progress that has been made in the functional analysis of more than half of the nuclear receptor gene family provides an opportunity to review the impact of genomics in this endeavor.

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Allosteric Binding Sites On Nuclear Receptors: Focus On Drug Efficacy and Selectivity

International Journal of Molecular Sciences ◽

10.3390/ijms21020534 ◽

2020 ◽

Vol 21 (2) ◽

pp. 534 ◽

Cited By ~ 1

Author(s):

André Fischer ◽

Martin Smieško

Keyword(s):

Nuclear Receptors ◽

Drug Targets ◽

Drug Efficacy ◽

Activation Function ◽

Resistance Mechanisms ◽

Solvent Mixtures ◽

Allosteric Inhibitors ◽

Binding Function ◽

Immunologic Diseases ◽

Dynamics Simulations

Nuclear receptors (NRs) are highly relevant drug targets in major indications such as oncologic, metabolic, reproductive, and immunologic diseases. However, currently, marketed drugs designed towards the orthosteric binding site of NRs often suffer from resistance mechanisms and poor selectivity. The identification of two superficial allosteric sites, activation function-2 (AF-2) and binding function-3 (BF-3), as novel drug targets sparked the development of inhibitors, while selectivity concerns due to a high conservation degree remained. To determine important pharmacophores and hydration sites among AF-2 and BF-3 of eight hormonal NRs, we systematically analyzed over 10 μ s of molecular dynamics simulations including simulations in explicit water and solvent mixtures. In addition, a library of over 300 allosteric inhibitors was evaluated by molecular docking. Based on our results, we suggest the BF-3 site to offer a higher potential for drug selectivity as opposed to the AF-2 site that is more conserved among the selected receptors. Detected similarities among the AF-2 sites of various NRs urge for a broader selectivity assessment in future studies. In combination with the Supplementary Material, this work provides a foundation to improve both selectivity and potency of allosteric inhibitors in a rational manner and increase the therapeutic applicability of this promising compound class.

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