Analysis of Pleurotin binding to human thioredoxin reductase using docking and molecular dynamics simulation
Related Experiment Video
Updated: Sep 6, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Daniel B Quintanilha1, Hélio F Dos Santos1
1NEQC: Núcleo de Estudos em Química Computacional, Departamento de Química, Universidade Federal de Juiz de Fora, Juiz de Fora, MG, Brazil.
Abstract:
Thioredoxin reductase (TrxR) has been considered a potential target for cancer chemotherapy. It acts by controlling the redox homeostasis of human cells and, therefore, interfering in its function may trigger apoptosis, which is a crucial tumor suppression mechanism. Despite the great effort in the search for TrxR inhibitors, none was approved for human therapy. In the present study a virtual screening for natural organic compounds is discussed for a set of 72 compounds with known IC-50 for TrxR inhibition. The results suggest the Pleurotin, a naphthoquinone obtained from Hohenbuehelia grisea fungus, as a potential TrxR inhibitor, which acts by binding to the active site of the enzyme, between the N- and C-terminal domains. The presence of the ligand blocks the approximation of the C-terminal arm to the N-terminal, which is an essential step of the enzyme function. Besides, the two equivalent binding sites of TrxR were explored, by docking two ligands simultaneously. The results indicate that both sites have an allosteric correlation and, the presence of the ligand in one site may interfere, or even prevent, the binding of the second ligand at the other site. All these findings are quantitatively discussed based on the analysis of long molecular dynamics trajectories, which provides a full description of the ligand-receptor binding modes, average binding energies and conformational changes.Communicated by Ramaswamy H. Sarma.
Insights
Pleurotin, a natural compound from Hohenbuehelia grisea fungus, shows potential as a thioredoxin reductase (TrxR) inhibitor. This discovery offers a new avenue for cancer chemotherapy by targeting cellular redox homeostasis.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Thioredoxin reductase (TrxR) is crucial for cellular redox homeostasis and a potential target for cancer chemotherapy.
- Interfering with TrxR function can induce apoptosis, a key tumor suppression mechanism.
- Despite extensive research, no TrxR inhibitors have been approved for human therapy.
Purpose of the Study:
- To identify novel natural organic compounds as potential TrxR inhibitors through virtual screening.
- To investigate the binding mechanism and allosteric effects of identified inhibitors.
- To provide quantitative insights into ligand-receptor interactions using molecular dynamics.
Main Methods:
- Virtual screening of 72 natural organic compounds with known IC-50 values for TrxR inhibition.
- Molecular docking to predict binding modes and interactions within the TrxR active site.
- Long molecular dynamics simulations to analyze binding energies and conformational changes.
Main Results:
- Pleurotin, a naphthoquinone from Hohenbuehelia grisea, was identified as a promising TrxR inhibitor.
- Pleurotin binds to the TrxR active site, hindering essential conformational changes required for enzyme function.
- Simultaneous docking revealed allosteric correlation between the two binding sites, where one ligand can impede the binding of another.
Conclusions:
- Pleurotin represents a potential lead compound for developing new cancer therapeutics targeting TrxR.
- Understanding the allosteric interactions of TrxR inhibitors is crucial for drug design.
- Molecular dynamics simulations offer a comprehensive approach to characterizing ligand-enzyme interactions.
More Related Videos
05:08Application of I TASSER, trRosetta, UCSF Chimera, HADDOCK server, and HEX loria for De Novo and In Silico Design of Proteins
Published on: July 8, 2025
05:57Author Spotlight: In Silico Creation and Impact of Carbonylated Amino Acids on Protein Structure and Function
Published on: April 26, 2024
Related Concept Videos
02:18The Equilibrium Binding Constant and Binding Strength
02:40Ligand Binding Sites
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...