Endocrine Disruption at the Androgen Receptor: Employing Molecular Dynamics and Docking for Improved Virtual Screening and Toxicity Prediction.

Joel Wahl,Martin Smieško

doi:10.3390/ijms19061784

Joel Wahl, Martin Smieško

Open Access

https://doi.org/10.3390/ijms19061784

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Abstract

The androgen receptor (AR) is a key target for the development of drugs targeting hormone-dependent prostate cancer, but has also an important role in endocrine disruption. Reliable prediction of the binding of ligands towards the AR is therefore of great relevance. Molecular docking is a powerful computational method for exploring small-ligand binding to proteins. It can be applied for virtual screening experiments but also for predicting molecular initiating events in toxicology. However, in case of AR, there is no antagonist-bound crystal structure yet available. Our study demonstrates that molecular docking approaches are not able to satisfactorily screen for AR antagonists because of this reason. Therefore, we applied Molecular Dynamics simulations to generate antagonist AR structures and showed that this leads to a vast improvement for the docking of AR antagonists. We benchmarked the ability of these antagonist AR structures discriminate between AR antagonists and decoys using an ensemble docking approach and obtained promising results with good enrichment. However, distinguishing AR antagonists from agonists with high confidence is not possible with the current approach alone.

Highlights

The androgen receptor (AR) is the main biomolecular target involved in the development and progression of the hormone-dependent prostate cancer [1]
Molecular Dynamics simulations in combination with molecular docking was applied to study the ability of structure-based screening methods to predict AR agonism and antagonism
Docking against an ensemble derived from experimental crystal structures of AR in agonist conformation was shown to yield good enrichments for the screening of agonists, but is insufficient for antagonist docking

Summary

Introduction

The androgen receptor (AR) is the main biomolecular target involved in the development and progression of the hormone-dependent prostate cancer [1]. In silico evaluation of small-molecule binding at the AR is of high relevance for the design of novel antiandrogens for the treatment of prostate cancer [1,4,5,6], and for the screening of potential androgen-disrupting chemicals [7] causing endocrine disorders [8,9]. A widely proposed mechanism for AR antagonism is the displacement of the Helix-12 (H12) upon ligand binding, leading to distortions in the AF2 site, preventing coactivator binding [13]. This mechanism was recently supported by computational studies employing Molecular Dynamics (MD) simulations [14,15,16]. The repositioning of H12 was confirmed to be the mechanism of antagonism for the estrogen receptor (ER) and the peroxisome proliferator-activated receptor (PPAR) [21]

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Results

Conclusion