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

André Fischer,Martin Smieško

doi:10.3390/ijms21020534

André Fischer, Martin Smieško

Open Access

https://doi.org/10.3390/ijms21020534

Copy DOI

Abstract

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 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.

Highlights

Nuclear receptors (NRs) are ligand-inducible transcription factors that are attractive drug targets due to their involvement in a multitude of physiological and pathological processes
The results suggest that the binding function-3 (BF-3) site offers a higher potential for the design of selective inhibitors due to the generally lower values in similarity among the receptors compared to the activation function-2 (AF-2)
The BF-3 site displayed advantages over the AF-2 site as a drug target in our analysis focused on sequence identity, pharmacophores, and hydration sites

Summary

Introduction

Nuclear receptors (NRs) are ligand-inducible transcription factors that are attractive drug targets due to their involvement in a multitude of physiological and pathological processes. The success of these therapeutics is often limited by poor selectivity and resistance mechanisms that, in the worst case, reverse the antagonistic effect of a drug and promote disease [3,4,5]. Two allosteric sites on the surface of several NRs, called activation function-2 (AF-2) and binding function-3 (BF-3), have been identified and considered as alternative sites for drug binding (Figure 1A). The AF-2 site corresponds to a protein–protein interaction surface for the binding of coactivator proteins essential for downstream signaling, which renders it an attractive target for potential inhibitors. Selectivity testing in the mentioned projects was, if conducted, in most cases, limited to a single other

Objectives

Methods

Results

Conclusion