Molecular View on the Dissociation Pathways and Transactivation Regulation Mechanism of Nonsteroidal GR Ligands

Abstract

As a major drug target for anti-inflammatory therapy, the glucocorticoid receptor (GR) regulates a wide range of physiological processes through transactivation (TA) or transrepression. GR TA is involved in many adverse effects of GR-targeting drugs, and therefore, the discovery of novel GR ligands with lower TA activity and longer residence time is quite urgent. Undoubtedly, understanding the ligand dissociation mechanisms and the structural basis of the TA regulation is crucial for the development of novel GR-targeting drugs. Here, we used random accelerated molecular dynamics (RAMD) and funnel metadynamics (FM) simulations to explore the dissociation mechanisms of 5 classic glucocorticoids and 6 nonsteroidal GR ligands. Multiple ligand dissociation pathways were discovered. The classic glucocorticoids exhibit a strong preference for Path I, and most nonsteroidal ligands tend to dissociate along mixed pathways. We also find that the distinct unbinding preferences for AZD2906 and AZD9567, two representative nonsteroidal ligands with similar scaffolds but different TA activities, are primarily determined by their different polar interactions with the surrounding residues. Notably, the binding of AZD9567 poses a substantial impact on the conformation of the GR homodimer interface, which provides a valuable clue to understand the mechanisms of the TA-related side effects induced by the adjustments of the homodimerization process. These findings are critical for the structure-based rational design of novel GR ligands with more potent anti-inflammatory potency and reduced side effects.

Discovery of Novel Anti‐Resistance AR Antagonists Guided by Funnel Metadynamics Simulation

“…Previous studies have indicated that the ligand entry pathway into the nuclear receptor involves a channel between helix‐3, helix‐7, and helix‐11. [ 24 ] Considering the possibility of alternative pathways for ligand dissociation from the nuclear receptor, [ 25 ] we first used the random accelerated MD (RAMD) [ 26 ] method to explore the dissociation pathways of the four ligands from the AR‐LBP. Each system was run with 40 parallel replicas, and the results are shown in Table S1 (Supporting Information).…”

Decoding Inhibitor Egression from Wild-Type and G2019S Mutant LRRK2 Kinase: Insights into Unbinding Mechanisms for Precision Drug Design in Parkinson’s Disease

“…A higher value of residence time increases the duration of drug action and leads to greater physiological inhibition. 77 Here, residence time (τ) was calculated from RAMD (it is not the physical residence time, but rather adaptive for the comparative study of residence time for inhibitors 78 ) for the inhibitors in each of the five kinase-inhibitor complexes (Figure S16). Comp1 showed a higher τ value (0.38 ns) in the WT system, whereas Comp2 showed a higher value (τ = 0.48 ns) for the mutated system (Table 3).…”

Exhaustively Exploring the Prevalent Interaction Pathways of Ligands Targeting the Ligand-Binding Pocket of Farnesoid X Receptor via Combined Enhanced Sampling

“…Nevertheless, because the biomacromolecule-relevant events often occur several orders of magnitude beyond a conventional MD (cMD) affordable simulation time, enhanced sampling techniques emerge, with algorithms such as random acceleration molecular dynamics (RAMD), umbrella sampling (US), metadynamics (MetaD), steered molecular dynamics (SMD), etc., widely applied in the tasks of identifying kinetic characteristics of drug-target interactions ( e.g. , the NR targets). − For instance, by using SMD and LES-MD simulations successively, Martinez et al revealed that the conformational rearrangement of the relevant residues in TRα/β leads to the dissociation of the ligand and furthermore interpreted the drug selectivity of the two NR targets. , Moreover, in a recent review, the authors summarized that the NRs may share several potential dissociation pathways because a similar fold structure is held by the NRs, but there are individual differences in certain NR members . However, most of the studies usually investigate a few systems ( e.g.…”