Advances in the computational development of androgen receptor antagonists

Hu, Xueping; Chai, Xin; Wang, Xuwen; Duan, Mojie; Pang, Jinping; Fu, Weitao; Li, Dan; Hou, Tingjun

doi:10.1016/j.drudis.2020.04.004

Cited by 23 publications

(9 citation statements)

References 65 publications

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“…Molecular dynamics (MD) simulation has been widely used to investigate the conformational dynamics and protein‐ligand interaction of NRs. [ 19 ] In 2020, Alves et al. employed steered MD simulations (SMD) and umbrella sampling to explore the transitions between the GR antagonist conformation and agonist conformation.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel GR Ligands toward Druggable GR Antagonist Conformations Identified by MD Simulations and Markov State Model Analysis

Pang

Zhang

et al. 2021

Advanced Science

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Binding of different ligands to glucocorticoid receptor (GR) may induce different conformational changes and even trigger completely opposite biological functions. To understand the allosteric communication within the GR ligand binding domain, the folding pathway of helix 12 (H12) induced by the binding of the agonist dexamethasone (DEX), antagonist RU486, and modulator AZD9567 are explored by molecular dynamics simulations and Markov state model analysis. The ligands can regulate the volume of the activation function‐2 through the residues Phe737 and Gln738. Without ligand or with agonist binding, H12 swings from inward to outward to visit different folding positions. However, the binding of RU486 or AZD9567 perturbs the structural state, and the passive antagonist state appears more stable. Structure‐based virtual screening and in vitro bioassays are used to discover novel GR ligands that bias the conformation equilibria toward the passive antagonist state. HP‐19 exhibits the best anti‐inflammatory activity (IC50 = 0.041 ± 0.011 µm) in nuclear factor‐kappa B signaling pathway, which is comparable to that of DEX. HP‐19 also does not induce adverse effect‐related transactivation functions of GR. The novel ligands discovered here may serve as promising starting points for the development of GR modulators.

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Section: Introductionmentioning

confidence: 99%

Discovery of Novel GR Ligands toward Druggable GR Antagonist Conformations Identified by MD Simulations and Markov State Model Analysis

Pang

Zhang

et al. 2021

Advanced Science

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“…Virtual screening is a powerful computational approach for the identification of lead compounds with novel structural scaffolds [ 28 , 29 ]. In this study, a method of structure-based virtual screening (SBVS) combined bioassays was employed to discover novel SGRMs.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a novel nonsteroidal selective glucocorticoid receptor modulator by virtual screening and bioassays

Pang

Liao

et al. 2022

Acta Pharmacol Sin

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Synthetic glucocorticoids (GCs) have been widely used in the treatment of a broad range of inflammatory diseases, but their clinic use is limited by undesired side effects such as metabolic disorders, osteoporosis, skin and muscle atrophies, mood disorders and hypothalamic-pituitary-adrenal (HPA) axis suppression. Selective glucocorticoid receptor modulators (SGRMs) are expected to have promising anti-inflammatory efficacy but with fewer side effects caused by GCs. Here, we reported HT-15, a prospective SGRM discovered by structure-based virtual screening (VS) and bioassays. HT-15 can selectively act on the NF-κB/AP1-mediated transrepression function of glucocorticoid receptor (GR) and repress the expression of pro-inflammation cytokines (i.e., IL-1β, IL-6, COX-2, and CCL-2) as effectively as dexamethasone (Dex). Compared with Dex, HT-15 shows less transactivation potency that is associated with the main adverse effects of synthetic GCs, and no cross activities with other nuclear receptors. Furthermore, HT-15 exhibits very weak inhibition on the ratio of OPG/RANKL. Therefore, it may reduce the side effects induced by normal GCs. The bioactive compound HT-15 can serve as a starting point for the development of novel therapeutics for high dose or long-term anti-inflammatory treatment.

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“…carried out microsecond unbiased MD simulations as well as bias-exchange metadynamics MD simulations to quantify the conformational characteristics of antagonist bound AR LBD 30 . Recently, Hu et al summarized the recent advances in the discovery of AR antagonists using computer-aided drug design approaches 31 . The computational analyses comprehensively support the mechanistic hypothesis that the AR antagonists cause conformational changes to the AR LBD, which can be correlated with the antagonism of the AR.…”

Section: Introductionmentioning

confidence: 99%

Conformational dynamics of androgen receptors bound to agonists and antagonists

Gim

Park

Jung

et al. 2021

Sci Rep

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The androgen receptor (AR) is critical in the progression of prostate cancer (PCa). Small molecule antagonists that bind to the ligand binding domain (LBD) of the AR have been successful in treating PCa. However, the structural basis by which the AR antagonists manifest their therapeutic efficacy remains unclear, due to the lack of detailed structural information of the AR bound to the antagonists. We have performed accelerated molecular dynamics (aMD) simulations of LBDs bound to a set of ligands including a natural substrate (dihydrotestosterone), an agonist (RU59063) and three antagonists (bicalutamide, enzalutamide and apalutamide) as well as in the absence of ligand (apo). We show that the binding of AR antagonists at the substrate binding pocket alter the dynamic fluctuations of H12, thereby disrupting the structural integrity of the agonistic conformation of AR. Two antagonists, enzalutamide and apalutamide, induce considerable structural changes to the agonist conformation of LBD, when bound close to H12 of AR LBD. When the antagonists bind to the pocket with different orientations having close contact with H11, no significant conformational changes were observed, suggesting the AR remains in the functionally activated (agonistic) state. The simulations on a drug resistance mutant F876L bound to enzalutamide demonstrated that the mutation stabilizes the agonistic conformation of AR LBD, which compromises the efficacy of the antagonists. Principal component analysis (PCA) of the structural fluctuations shows that the binding of enzalutamide and apalutamide induce conformational fluctuations in the AR, which are markedly different from those caused by the agonist as well as another antagonist, bicalutamide. These fluctuations could only be observed with the use of aMD.

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Advances in the computational development of androgen receptor antagonists

Cited by 23 publications

References 65 publications

Discovery of Novel GR Ligands toward Druggable GR Antagonist Conformations Identified by MD Simulations and Markov State Model Analysis

Discovery of Novel GR Ligands toward Druggable GR Antagonist Conformations Identified by MD Simulations and Markov State Model Analysis

Discovery of a novel nonsteroidal selective glucocorticoid receptor modulator by virtual screening and bioassays

Conformational dynamics of androgen receptors bound to agonists and antagonists

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