scholarly journals Molecular Mechanism of Action of RORγt Agonists and Inverse Agonists: Insights from Molecular Dynamics Simulation

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3181 ◽  
Author(s):  
Nannan Sun ◽  
Congmin Yuan ◽  
Xiaojun Ma ◽  
Yonghui Wang ◽  
Xianfeng Gu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Mechanism ◽  
Mechanism Of Action ◽  
Critical Role ◽  
Inverse Agonist ◽  
Orphan Receptor ◽  
Dynamics Simulation ◽  
Side Chain ◽  
Trans Conformation ◽  
Molecular Mechanism Of Action

As an attractive drug-target, retinoic acid receptor-related orphan receptor-gamma-t (RORγt) has been employed widely to develop clinically relevant small molecular modulators as potent therapy for autoimmune disease and cancer, but its molecular mechanism of action (MOA) remains unclear. In the present study, we designed and discovered two novel RORγt ligands that are similar in structure, but different in efficacy. Using fluorescence resonance energy transfer (FRET) assay, compound 1 was identified as an agonist with an EC50 of 3.7 μM (max. act.: 78%), while compound 2 as an inverse agonist with an IC50 value of 2.0 μM (max. inh.: 61%). We performed molecular dynamics (MD) simulations, and elucidated the MOA of RORγt agonist and inverse agonist. Through the analyses of our MD results, we found that, after RORγt is bound with the agonist 1, the side chain of Trp317 stays in the gauche- conformation, and thus helps to form the hydrogen bond, His479-Trp502, and a large hydrophobic network among H11, H11′, and H12. All these interactions stabilize the H12, and helps the receptor recruit the coactivator. When the RORγt is bound with the inverse agonist 2, the side chain of Trp317 is forced to adopt the trans conformation, and these presumed interactions are partially destroyed. Taken together, the critical role of residue Trp317 could be viewed as the driving force for the activation of RORγt.

Diacylfuroxans Are Masked Nitrile Oxides That Inhibit GPX4 Covalently

2019 ◽  
Author(s):  
John Eaton ◽  
Richard A. Ruberto ◽  
Anneke Kramm ◽  
Vasanthi S. Viswanathan ◽  
Stuart Schreiber
Keyword(s):  
Molecular Mechanism ◽  
Mechanism Of Action ◽  
Therapeutic Target ◽  
Biologically Active ◽  
Drug Resistant ◽  
Nitrile Oxides ◽  
Molecular Mechanism Of Action

<div><div><div><p>GPX4 represents a promising yet difficult-to-drug therapeutic target for the treatment of, among others, drug-resistant cancers. While most GPX4 inhibitors rely on a chloroacetamide moiety to modify covalently the protein’s catalytic selenocysteine residue, the discovery and mechanistic elucidation of structurally diverse GPX4-inhibiting molecules has uncovered novel electrophilic warheads that bind and inhibit GPX4. Here we report our discovery that diacylfuroxans can act as masked nitrile oxides that inhibit GPX4 covalently. These observations illuminate a novel molecular mechanism of action for biologically active furoxans and also suggest that nitrile oxides may be uniquely suited to targeting GPX4.</p></div></div></div>

Dietary selenomethionine ameliorates lipopolysaccharide-induced renal inflammatory injury in broilers via regulating the PI3K/AKT pathway to inhibit necroptosis

2021 ◽  
Author(s):  
Yue Zhang ◽  
Xue Qi ◽  
Xiaoming Chen ◽  
Jinxi Zhang ◽  
Wenyue Zhang ◽  
...  
Keyword(s):  
Protective Effect ◽  
Molecular Mechanism ◽  
Mechanism Of Action ◽  
Kidney Tissue ◽  
Akt Pathway ◽  
Inflammatory Injury ◽  
Molecular Mechanism Of Action

We explore the protective effect of dietary SeMet on the kidney tissue of broilers and determine its potential molecular mechanism of action.

Cellular and molecular mechanism of action of raloxifene on vascular tissue

Bone ◽  
2007 ◽  
Vol 41 (6) ◽  
pp. S2
Author(s):  
B Rauschemberger ◽  
P Cutini ◽  
M Sandoval ◽  
N Polini ◽  
V Massheimer
Keyword(s):  
Molecular Mechanism ◽  
Mechanism Of Action ◽  
Vascular Tissue ◽  
Molecular Mechanism Of Action

scholarly journals Prediction of GluN2B-CT1290-1310/DAPK1 Interaction by Protein–Peptide Docking and Molecular Dynamics Simulation

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 3018 ◽  
Author(s):  
Gao Tu ◽  
Tingting Fu ◽  
Fengyuan Yang ◽  
Lixia Yao ◽  
Weiwei Xue ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Electrostatic Interactions ◽  
Binding Free Energy ◽  
Computational Simulation ◽  
Critical Role ◽  
Dynamics Simulation ◽  
Peptide Docking ◽  
C Terminus ◽  
Free Energy Decomposition

The interaction of death-associated protein kinase 1 (DAPK1) with the 2B subunit (GluN2B) C-terminus of N-methyl-D-aspartate receptor (NMDAR) plays a critical role in the pathophysiology of depression and is considered a potential target for the structure-based discovery of new antidepressants. However, the 3D structures of C-terminus residues 1290–1310 of GluN2B (GluN2B-CT1290-1310) remain elusive and the interaction between GluN2B-CT1290-1310 and DAPK1 is unknown. In this study, the mechanism of interaction between DAPK1 and GluN2B-CT1290-1310 was predicted by computational simulation methods including protein–peptide docking and molecular dynamics (MD) simulation. Based on the equilibrated MD trajectory, the total binding free energy between GluN2B-CT1290-1310 and DAPK1 was computed by the mechanics generalized born surface area (MM/GBSA) approach. The simulation results showed that hydrophobic, van der Waals, and electrostatic interactions are responsible for the binding of GluN2B-CT1290–1310/DAPK1. Moreover, through per-residue free energy decomposition and in silico alanine scanning analysis, hotspot residues between GluN2B-CT1290-1310 and DAPK1 interface were identified. In conclusion, this work predicted the binding mode and quantitatively characterized the protein–peptide interface, which will aid in the discovery of novel drugs targeting the GluN2B-CT1290-1310 and DAPK1 interface.

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