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Protein kinase Cβ (PKCβ) is considered as an attractive molecular target for the treatment of COVID-19-related acute respiratory distress syndrome (ARDS). Several classes of inhibitors have been already identified. In this article, we developed and validated ligand-based PKCβ pharmacophore models based on the chemical structures of the known inhibitors. The most accurate pharmacophore model, which correctly predicted more than 70% active compounds of test set, included three aromatic pharmacophore features without vectors, one hydrogen bond acceptor pharmacophore feature, one hydrophobic pharmacophore feature and 158 excluded volumes. This pharmacophore model was used for virtual screening of compound collection in order to identify novel potent PKCβ inhibitors. Also, molecular docking of compound collection was performed and 28 compounds which were selected simultaneously by two approaches as top-scored were proposed for further biological research. [ABSTRACT FROM AUTHOR]

Apoptosis signal-regulating kinase 1 (ASK1) has recently emerged as an attractive molecular target for pharmaceutical intervention. Several classes of small-molecular ASK1 inhibitors have been identified. In this article, we analysed the binding of small-molecular inhibitors from different chemotypes with ASK1 using molecular dynamic simulations. The umbrella sampling technique was used to calculate the binding free energy (ΔG) for these compounds with ASK1 ATP-binding pocket. According to the obtained results, umbrella sampling gave correct ranking of the binding affinities for investigated inhibitors relative to their experimental pIC50 values and can be useful for further structure-based design of ASK1 inhibitors to accelerate lead optimisation. Trial registration: ClinicalTrials.gov identifier: NCT02466516.. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus (S. aureus) is a causative agent of many hospital- and community-acquired infections with the tendency to develop resistance to all known antibiotics. Therefore, the development of novel antistaphylococcal agents is of urgent need. Sortase A is considered a promising molecular target for the development of antistaphylococcal agents. The main aim of this study was to identify novel sortase A inhibitors. In order to find novel antistaphylococcal agents, we performed phenotypic screening of a library containing 15512 compounds against S. aureus ATCC43300. The molecular docking of hits was performed using the DOCK program and 10 compounds were selected for in vitro enzymatic activity inhibition assay. Two inhibitors were identified, N,N-diethyl-N′-(5-nitro-2-(quinazolin-2-yl)phenyl)propane-1,3-diamine (1) and acridin-9-yl-(1H-benzoimidazol-5-yl)-amine (2), which decrease sortase A activity with IC50 values of 160.3 µM and 207.01 µM, respectively. It was found that compounds 1 and 2 possess antibacterial activity toward 29 tested multidrug resistant S. aureus strains with MIC values ranging from 78.12 to 312.5 mg/L. These compounds can be used for further structural optimization and biological research. [ABSTRACT FROM AUTHOR]