Serine/threonine protein kinase CK2 controls vast variety of fundamental processes in cell life; however, despite long period of study, its functional role is not completely determined. CK2 has a significant pathogenic potential and its activity is strictly associated with the development of various kinds of disorders. There are a growing number of facts that inhibitors of CK2 could be used as pharmaceutical agents for the cancer treatment, viral infections, and inflammatory diseases. In this article, we report structural and biological data on the novel synthetic flavonol derivatives, 3-hydroxy-4'-carboxyflavones, possessing a high inhibitory activity toward CK2. With the aid of combinatorial organic synthesis, molecular modeling techniques and biochemical in vitro tests, we studied the structure-activity relationships of flavonol derivatives and developed binding model describing their key intermolecular interactions with the CK2 ATP-binding site. Obtained data show that the synthetic 3-hydroxy-4'-carboxyflavones possess the highest activity among flavonol inhibitors of CK2 known till date.

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Protein kinase CK2 is associated with a number of human diseases, among them cancer, and is therefore a target for inhibitor development in industry and academia. Six crystal structures of either CK2α, the catalytic subunit of human protein kinase CK2, or its paralog CK2α′ in complex with two ATP-competitive inhibitors—based on either a flavonol or a thieno[2,3-d]pyrimidine framework—are presented. The structures show examples for extreme structural deformations of the ATP-binding loop and its neighbourhood and of the hinge/helix αD region, i.e., of two zones of the broader ATP site environment. Thus, they supplement our picture of the conformational space available for CK2α and CK2α′. Further, they document the potential of synthetic ligands to trap unusual conformations of the enzymes and allow to envision a new generation of inhibitors that stabilize such conformations.

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Staphylococcus aureus is one of the most dangerous pathogens commonly associated with high levels of morbidity and mortality. Sortase A is considered as a promising molecular target for the development of antistaphylococcal agents. Using hybrid virtual screening approach and FRET analysis, we have identified five compounds able to decrease the activity of sortase A by more than 50% at the concentration of 200 µM. The most promising compound was 2-(2-amino-3-chloro-benzoylamino)-benzoic acid which was able to inhibit S. aureus sortase A at the IC 50 value of 59.7 µM. This compound was selective toward sortase A compared to other four cysteine proteases – cathepsin L, cathepsin B, rhodesain, and the SARS-CoV2 main protease. Microscale thermophoresis experiments confirmed that this compound bound sortase A with K D value of 189 µM. Antibacterial and antibiofilm assays also confirmed high specificity of the hit compound against two standard and three wild-type, S. aureus hospital infection isolates. The effect of the compound on biofilms produced by two S. aureus ATCC strains was also observed suggesting that the compound reduced biofilm formation by changing the biofilm structure and thickness.

Protein kinase CK2 (Casein Kinase 2) is a ubiquitous serine/threonine protein kinase involved in various cell signal transduction pathways. Thus, CK2 is a new perspective target for anticancer drugs. The receptor-based virtual screening of 2000 compounds from combinatorial library of 4H-4-chromenones has been carried out in search for CK2-inhibitors. 90 compounds have been chosen for biological testing based on the score values calculated by DOCK 4.0 software. It has been revealed, that 3-(4-chloro-3,5dimethylphenoxy)-7-(4-methoxyphenylcarbonyloxy)-4-oxo-4H-chromene (12) and 7-(4-fluorophenylcarbonyloxy)-4-oxo-3-(4-phenylphenoxy)-4H-chromene (14) inhibit CK2 activity with /C50-18.8 pM and ICso-22.4 fiM, respectively.

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Background: The most serious challenge in the treatment of tuberculosis is the multidrug resistance of Mycobacterium tuberculosis to existing antibiotics. As a strategy to overcome resistance we used a multitarget drug design approach. The purpose of the work was to discover dual-targeted inhibitors of mycobacterial LeuRS and MetRS with machine learning. Methods: The artificial neural networks were built using module nnet from R 3.6.1. The inhibitory activity of compounds toward LeuRS and MetRS was investigated in aminoacylation assays. Results: Using a machine-learning approach, we identified dual-targeted inhibitors of LeuRS and MetRS among 2-(quinolin-2-ylsulfanyl)-acetamide derivatives. The most active compound inhibits MetRS and LeuRS with IC50 values of 33 μm and 23.9 μm, respectively. Conclusion: 2-(Quinolin-2-ylsulfanyl)-acetamide scaffold can be useful for further research.