Structural Dynamics of Agonist and Antagonist Binding to the Androgen Receptor

Abstract

Androgen receptor (AR) is a steroid hormone nuclear receptor which upon binding its endogenous androgenic ligands (agonists), testosterone and dihydrotestosterone (DHT), alters gene transcription producing a diverse range of biological effects. Anti-androgens, such as the pharmaceuticals bicalutamide and hydroxyflutamide, act as agonists in the absence of androgens and as antagonists in their presence or in high concentration. The atomic level mechanism of action by agonists and antagonists of AR is less well characterized. Therefore, in this study, multiple 1 µs molecular dynamics (MD), docking simulations and perturbation-response analyses were performed to more fully explore the nature of interaction between agonist or antagonist and AR and the conformational changes induced in the AR upon interaction with different ligands. We characterized the mechanism of the ligand entry/exit and found that Helix-12 and nearby structural motifs respond dynamically in that process. Modeling showed that the agonist and antagonist/ agonist form a hydrogen bond with Thr877/Asn705 and that this interaction is absent for antagonists. Agonist binding to AR increases mobility of residues at allosteric sites and coactivator binding sites, while antagonist binding decreases mobility at these important sites. A new site was also identified as a potential surface for allosteric binding. These results shed light on the effect of agonists and antagonists on the structure and dynamics of AR.

Steroids and TRP Channels: A Close Relationship

“…This pocket shows similitude to the cavity used by testosterone in the aromatase (an enzyme that also binds testosterone to convert it into 17β estradiol) [183]. Additionally, it has been reported that testosterone binds to the AR through a H-bond with an arginine (R752) [184], similarly to the H-bond predicted for the interaction with the TRPM8 channel. These reports strengthen the idea that the pocket for testosterone predicted in the TRPM8 channel could be functional and that it is located between the preS1 and S1-S2, where testosterone could establish hydrophobic interaction with these regions.…”

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…In contrast to multi-pass (integral) membrane proteins, where considerable work has been performed, in particular the GPCR class of membrane proteins e.g., [885][886][887][888][889][890][891][892][893][894][895][896][897][898][899] (for review see references: [31,[900][901][902][903]), that are a very hot topic, peripheral and bitopic (single pass) membrane proteins, which constitute 43-45% of transmembrane proteins [883], are underrepresented in MD simulation studies.…”

Molecular Image-Based Prediction Models of Nuclear Receptor Agonists and Antagonists Using the DeepSnap-Deep Learning Approach with the Tox21 10K Library

“…In the absence of a ligand, the type I NR forms inactive complexes with chaperone proteins in the cytoplasm, whereas type II NR, regardless of the ligand-binding status, is located in the nucleus and binds to the DNA response elements of its target genes along with corepressors [6,14,16]. For these types of NRs, a number of allosteric modulators have been identified that can act as either agonist or antagonist by occupying the active pocket of the NR and blocking the recruitment of coactivators or corepressors to the transcriptional complex [11,[17][18][19][20].…”

“…The perturbation of the NR signaling pathway due to the action of agonists or antagonists of chemical compounds is associated with various adverse health outcomes [19,21]. Although chemical hazard assessments have traditionally relied upon toxicity data from animal bioassays and epidemiological studies, there are some drawbacks to this testing method, such as high cost, lengthy test durations, and ethical concerns [5,[22][23][24][25][26][27].…”