Search

Aim. To identify novel protein kinase CK2 inhibitors among the 5-hetarylamino-1H-indazoles. Methods. Biochemical testing was carried out with the aid of γ-32P ATP in vitro kinase assay. Molecular docking via the Autodock 4.2.6 program package was executed, rescoring of docking results was performed using DrugScore scoring function. Results. Among the 17 studied 5-amino-3-arylindazole derivatives 11 inhibitors of protein kinase CK2 with IC50 in nanomolar range were identified. The most active compound has IC50 = 2 nM. SAR study and additional molecular modeling of these compounds allowed us to select prospective substituents for construction of novel compounds with improved activity and physicochemical properties. Conclusions. As a result of this work 11 nanomolar protein kinase CK2 inhibitors were developed and the binding modes of these compounds with the ATP-acceptor site were proposed using molecular docking methods. The physicochemical properties and SAR of substituents of studied compounds were analyzed and 6 novel compounds were designed for further development as protein kinase CK2 inhibitors. Summarizing, 5-heterylamino-1H-indazoles are a good basis for further CK2 inhibitors development. [ABSTRACT FROM AUTHOR]

Aim. Basing on our earlier finding of inhibitory activity of 5-(4-quinazolylamino)-3-arylindazoles against human protein kinase CK2, the synthesis of new nitrogen containing heterocyclic derivatives was performed in order to find novel inhibitors of this kinase. Methods. Organic synthesis, NMR spectroscopy. Results. A series of 4-chloroquinazolines, 4-chloroquinolines, 4-chloropyrazolo[3,4-d]pyrimidines and 4-chlorothieno[2,3-d]pyrimidine was synthesized. Reaction of these intermediates with 5-amino-3-(3,4-dichlorophenyl)-indazole gave us a series of 14 novel heterocyclic derivatives of 5-amino-3-arylindazole. Conclusions. Besides new quinazoline derivatives -- the quinoline and thieno[2,3-d]pyrimidine derivatives of similar structure but different polarity were obtained. Also a series of 1-methylpyrazolo[3,4-d]pyrimidine derivatives with decreased lipophilicity was synthesized. [ABSTRACT FROM AUTHOR]

Aim. To identify novel FGFR1 inhibitors using the virtual screening approach. Methods. Virtual screening of a small organic compounds library was performed by molecular docking using the Autodock 4.2.6 program package. The compounds activity was determined by in vitro biochemical tests using γ-32P ATP. Results. In vitro experiments demonstrated that 18 compounds belonging to three chemical classes had an inhibitory activity against FGFR1 with IC50 values in the range from 1.8 to 71 μM. Conclusions. Several FGFR1 inhibitors were found using molecular modeling and biochemical testing. These compounds are excellent candidates for further chemical optimization. [ABSTRACT FROM AUTHOR]

Aim. To search for new CK2 inhibitors by virtual screening. Methods. Virtual screening of a small organic compounds library was performed by molecular docking using the Autodock 4.2.6 package and pharmacophore screening with the “PharmDeveloper” program. The compound activity was determined by in vitro biochemical tests using γ-P32 ATP. Results. 298 compounds were selected for biochemical testing according to the results of virtual screening. In vitro experiments showed that 18 compounds have inhibitory activity against CK2 with IC50 in the range of 1.4 to 20 μM. The active compounds belonged to 15 chemical classes. Conclusions. A number of effective CK2 inhibitors were found using molecular modeling and biochemical testing methods. LE values of these compounds were higher than 0.3 that makes these compounds excellent candidates for further drug development. [ABSTRACT FROM AUTHOR]

The search of CK2 inhibitors was performed by using virtual screening approach and in vitro kinase assay. We have found 2 compounds inhibiting protein kinase in micromolar range. The most active compound was N-(6-methoxybenzo[d]thiazol-2-yl)-2-(tetrazolo[1,5-c]quinazolin-5-ylthio)acetamide (1С50=4,9 μM). Binding mode for tested inhibitors with CK2 ATP-binding site has been proposed. [ABSTRACT FROM AUTHOR]

Aim. Development of receptor-based pharmacophore model for protein kinase Cβ (PKCβ). Methods. Pharmacophore modeling was performed with Discovery Studio Visualizer 4.0 and PharmDeveloper software. Results. The resulted pharamacophore model consisted of five pharamacophore features, two aromatic features without vectors, two acceptors of hydrogen bonds, one donor of acceptor bond, was generated and validated. Conclusion. This pharmacophore model will be used for virtual screening of compound collection in order to identify potential inhibitors of PKCβ. [ABSTRACT FROM AUTHOR]

Aim. To identify novel putative drug targets of methicillin-resistant S. aureus (MRSA) through subtractive proteome analysis. Methods. Identification of non-homologous proteins in the human proteome, search of MRSA essential genes and evaluation of drug target novelty were performed using a protein BLAST server. Unique metabolic pathways identi- fication was carried out using data and tools from KEGG (Kyoto Encyclopedia of Genes and Genomes). Prediction of sub-cellular proteins localization was performed using combination of PSORT v. 3.0.2, CELLO v. 2.5, iLoc-Gpos, and Pred-Lipo tools. Homology modeling was performed using SWISS-MODEL, Phyre2, I-TASSER web-servers and the MODELLER software. Results. Proteomes of six annotated methicillin-resistant strains : MRSA ATCC BAA-1680, H-EMRSA-15, LA MRSA ST398, MRSA 252, MRSA ST772, UTSW MRSA 55 were initially analyzed. The proteome analysis of the MRSA strains in several consequent steps allowed to identify two molecular targets: diadenylate cyclase and D-alanyl-lipoteichoic acid biosynthesis (DltB) protein which meet the requirements of being essential, membrane-bound, non-homologous to human proteome, involved in unique metabolic pathways and new in terms of not having approved drugs. Using the homology modeling approach, we have built three-dimensional structures of these proteins and predicted their ligand-binding sites. Conclusions. We used classical bioinformatics approaches to identify two molecular targets of MRSA :diadenylate cyclase and DltB which can be used for further rational drug design in order to find novel therapeutic agents for treatment of multidrug resistant staphylococcal infection. [ABSTRACT FROM AUTHOR]

Pharmacophore modeling is modern efficient approach which is widely used in drug discovery. This method has several drawbacks. First of all, pharmacophore models are not selective to structurally similar compounds that belong to one chemical class but possess different activity. Another drawback is that during pharmacophore screening a number of non-active compounds can be selected in the top of results. We have developed novel algorithm for pharmacophore model optimization and for rescoring of pharmacophore screening results. The advantages of our algorithm are optimization of pharmacophore feature radii, application of the concept of pharmacophore feature weights and molecular descriptors. The algorithm was validated based on pharmacophore models of FGFR1 and CK2 inhibitors. In the case of FGFR1 pharmacophore model, the application of algorithm allowed to increase the number of active compounds identified during screening of validation set from 21 to 43 and percent of correctly found active compounds in the top was increased from 38 to 60%. In the case of CK2 pharmacophore model, the number of active compounds identified during screening of validation set increased from 12 to 39 and percent of correctly found active compounds in the top increased from 58 to 74%. [ABSTRACT FROM AUTHOR]

Aim. To synthesize the novel purine bioisosteres -- indazole derivatives and evaluate inhibitory activity of these compounds towards CK2 in the in vitro system. Methods. Chemical synthesis, 1H and 13C NMR spectroscopy, LC-MS method, determination of residual enzyme activity using ATP consumption tests with a luciferase Kinase-Glo® luminescent kinase assay. Results. Known synthetic methods of indazole chemistry were originally applied to the synthesis of 3-aryl-indazole-7-carboxylic acids. Conditions of cross-coupling of 3-bromo-indazole derivatives with arylboronic acids were substantially improved. 3-aryl-indazole 5- and 7-carboxylic acids have shown IC50 in a range 3.1-6.5 μM in luciferase luminescent kinase assay. Conclusions. The synthesis of 3-aryl-indazole-7-carboxylic acids has been developed. Novel inhibitors of the protein kinase CK2 among indazole derivatives have been identified among the 3-aryl-indazole 5- and 7-carboxylic acids. It has been shown the crucial impact of carboxyl group on the inhibitory activity of studied compounds. [ABSTRACT FROM AUTHOR]

Aim. A search for human protein kinase CK2 inhibitors in a series of new amino-substituted pyrido[2,3-d]pyrimidine derivatives. Methods. Organic synthesis, analytical and spectral methods, molecular docking, in vitro biochemical testing. Results. Synthesis of new pyrido[2,3- d]pyrimidine derivatives with various aminogroups in position[s] 4 and 6 of the heterocycle was developed. Two compounds inhibiting kinase CK2 in micromolar concentrations were found among these derivatives. Conclusion. New pyrido[2,3-d]pyrimidin-7-ones containing aminogroups in position[s] 4 and 6 of heterocyclic system and new 4-amino-substituted pyrido[2,3-d]pyrimidin-7-amine derivatives have been synthesized. The inhibition activity of new pyrido[2,3-d]pyrimidines has been examined and the optimization modes have been suggested. Methyl-2-[(7-aminopyrido[2,3-d]pyrimidine-6-yl)amino]benzoate and N-(4-anilino-7- oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-yl)-3,4-dimethoxy- benzamide were found to inhibit protein kinase CK2 at IC50 of 6 and 19.5 μМ, respectively. [ABSTRACT FROM AUTHOR]

Twenty derivatives of the 1-benzyl-3-chloro-4-anilino-2,5-dihydro-1H-2,5-piroldion with different substituents at aniline and benzene rings were synthesized and tested for cytotoxic activity. Compounds were tested on cancer cell lines HCT-15, MSF7, Hs683, U-373MG, LoVo and A549. Five compounds were shown to inhibit the proliferation of cancer cells with IC50>5x10-6M. [ABSTRACT FROM AUTHOR]

The search of inhibitors of protein kinase CK2 among 2-pyridone derivatives via receptor-based virtual screening and biochemical tests in vitro was carried out. It was found that one inhibitor from 15 selected compoundshave IC50=8.3 µM. The binding mode of this ligand with amino acid residue of ATP-acceptor site of protein kinase CK2 has been proposed. [ABSTRACT FROM AUTHOR]