Molecular docking studies of salubrinal and its analogs as inhibitors of the GADD34:PP1 enzyme

Abstract

<jats:p>&lt;p class="ADMETabstracttext"&gt;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.&lt;/p&gt;</jats:p>

Structural and mechanistic insights intoPlasmodiumeIF2alpha dephosphorylation by UIS2 during the erythrocytic stage

“…Our findings also suggest that salubrinal competes with the S59-loop for binding to the surface cavity within UIS2-PD, thereby inhibiting protein-protein interaction. This aligns with a previous molecular docking study showing that salubrinal can fit into the catalytic pocket of GADD34/PP1 (41). Moreover, salubrinal inhibits P-eIF2alpha dephosphorylation in human cells by disrupting the formation of the GADD34/PP1 complex (42).…”

ER stress in mouse serotonin neurons triggers a depressive phenotype alleviated by ketamine targeting eIF2α signaling

“… 68 In addition, eIF2α-dependent translation is a key molecular process underlying synaptic plasticity. 36 , 37 , 69 , 70 Therefore, we further explored whether the disruption of PERK-eIF2α signaling pathway, and eventually eEF2, prevents the antidepressant action of ketamine in the Tm-induced ERS mouse model in DR. We used the small molecule ISRIB (integrated stress response inhibitor), which blocks downstream p -eIF2α signaling under ERS or salubrinal (SAL), an eIF2α dephosphorylation inhibitor (eIF2α-GADD34:PP1 phosphatase inhibitor) 71 , 72 , 73 ( Figure 5 A). While treatment with ISRIB (0.25 mg/kg, ip, two doses) facilitated ketamine-induced reversal of BiP levels in DR after local ERS, SAL (1 mg/kg, ip, two doses) prevented the effect of ketamine, and mice treated with Tm+SAL+Ket showed a marked increase in BiP protein levels compared to Tm+Ket-treated mice ( Figure 5 B).…”

Synthesis, Anti-Inflammatory Activity and Molecular Docking Studies of 1,4,5,6-Tetrahydropyrimidine-2-Carboxamides

“…Prior to molecular docking, the structures of all test compounds 1-14 were optimized in the semi-empirical PM3 method 54 using the ArgusLab 4.0.1 software package. [55][56][57][58][59][60][61][62][63][64]…”