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Molecular docking studies of salubrinal and its analogs as inhibitors of the GADD34:PP1 enzyme
Pavlo V Zadorozhnii1, Ihor O Pokotylo1, Vadym V Kiselev1
1Department of Organic Substances and Pharmaceutical Preparations, Ukrainian State University of Chemical Technology, Gagarin Ave., 8, Dnipro 49005, Ukraine.
Abstract:
The phenomenon of the endoplasmic reticulum (ER) stress as a molecular pathophysiological process underlies diseases as cancer, diabetes mellitus, myocardial infarction, neurodegenerative disorders, diseases of the urinary system, disorders associated with bone integrity, etc. To prevent ER stress, salubrinal, which is a phosphatase inhibitor of the eukaryotic translation initiation factor - GADD34:PP1, is currently being intensively studied. The aim of this work is to search for new analogues of this drug using molecular docking methods. Optimization of the geometry of the studied structures and molecular docking was carried out using the ArgusLab 4.0.1 software package. The three-dimensional crystal structure of the GADD34: PP1 enzyme (PDB ID: 4XPN) was loaded in the PDB format from the protein molecule data bank. The model of the binding site was created on the basis of the phosphoric acid residue (403 PO4). The dimensions of the binding site were set manually and were 40.000 Å along the X-axis, 40.000 Å - the Y-axis and 40.000 Å - the Z-axis. The docking was done with a flexible ligand, and the semi-empirical AScore function was used for the scoring procedure. It was shown that for the salubrinal molecule the most favorable was the conformation stabilized by the intramolecular hydrogen bond formed between the hydrogen atom of the thiourea fragment and the oxygen atom of the amide fragment. According to molecular docking data, six compounds from the fifty-four analyzed analogues of salubrinal exceed it in the stability of the complex formed with GADD34:PP1. The results of this work can be used to create new phosphatase inhibitors of the eukaryotic translation initiation factor GADD34:PP1.
Insights
Researchers explored new drug analogues to combat endoplasmic reticulum (ER) stress, a factor in many diseases. Molecular docking identified six salubrinal analogues with stronger binding to the GADD34:PP1 enzyme, offering potential new treatments.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Endoplasmic reticulum (ER) stress is a key molecular process implicated in numerous diseases, including cancer, diabetes, and neurodegenerative disorders.
- Salubrinal, a phosphatase inhibitor targeting the eukaryotic translation initiation factor GADD34:PP1, is under investigation for ER stress prevention.
- Developing novel GADD34:PP1 inhibitors is crucial for therapeutic interventions against ER stress-related pathologies.
Purpose of the Study:
- To identify novel analogues of salubrinal with enhanced binding affinity to the GADD34:PP1 enzyme.
- To utilize molecular docking methods for the virtual screening and design of potential therapeutic agents.
- To explore new chemical entities for inhibiting GADD34:PP1 activity and mitigating ER stress.
Main Methods:
- Molecular docking simulations were performed using the ArgusLab 4.0.1 software package.
- The crystal structure of the GADD34:PP1 enzyme (PDB ID: 4XPN) was used as the target.
- A binding site model was created, and docking was conducted with flexible ligands using the AScore function for scoring.
Main Results:
- The most stable conformation of salubrinal was identified, stabilized by an intramolecular hydrogen bond.
- Molecular docking analysis revealed six out of fifty-four analyzed salubrinal analogues demonstrated superior binding complex stability with GADD34:PP1.
- These novel analogues showed greater potential for inhibiting GADD34:PP1 compared to salubrinal itself.
Conclusions:
- The study successfully identified promising new analogues of salubrinal with enhanced GADD34:PP1 inhibitory potential.
- These findings provide a basis for the development of novel therapeutics targeting ER stress-related diseases.
- The identified compounds represent valuable leads for future drug development efforts in this area.
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