This work reports on a complex in silico assessment of the ADME properties of Salubrinal (S1) and 54 of its structural analogues containing a cinnamic acid residue (S2–S40) or a quinoline ring (S41–S55). In the work for (Q)SAR forecast, the online servers SwissADME, ADMETlab, admetSAR 2.0, Molinspiration, ALOGPS 2.1, pkCSM, SuperCYPsPred, and Vienna LiverTox were used. In addition, using AutoDock Vina, molecular docking studies were performed with transporter proteins and metabolic enzymes, which were intended to interact with the test compounds. In silico assessment of the ability of the S1–S55 compounds to be absorbed in the intestine was carried out using the SAR classification models implemented in these servers, as well as on the basis of two empirical rules—Lipinski’s and Veber’s. Most of the studied compounds had moderate lipophilicity (MLogP ˂ 4.15) and a polar surface area of less than 140 Å2. They complied with Lipinski’s and Veber’s rules, and are predicted to have good intestinal absorption. In silico analysis of the distribution of the S1–S55 compounds throughout the body, the volume of distribution at steady-state (Vdss), the ability to bind to blood plasma proteins and cross the blood-brain barrier (BBB) were taken into account. Most compounds are predicted to have low or medium Vdss and the ability to cross the BBB. Molecular docking studies were carried out with the structures most important for drug binding of blood plasma proteins, human serum albumin (HSA), and alpha-1-acid glycoprotein (AGP). The studies showed that these substances can effectively bind to blood plasma proteins. When assessing metabolism, the prediction of inhibitory and substrate activity to cytochromes P450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) was carried out. For most of these enzymes, the analyzed compounds are likely to be potential inhibitors, as indicated by the molecular docking data. For all studied compounds, a low total clearance (CLtot. ˂ 5 mL/min/kg) and a half-life time (T1/2 ˂ 3 h) are predicted.

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A new, simple method for the synthesis of 4

<p class="ADMETabstracttext">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.</p>