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1.
RSC Adv ; 14(2): 1341-1353, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38174256

RESUMO

This study introduces the PocketCFDM generative diffusion model, aimed at improving the prediction of small molecule poses in the protein binding pockets. The model utilizes a novel data augmentation technique, involving the creation of numerous artificial binding pockets that mimic the statistical patterns of non-bond interactions found in actual protein-ligand complexes. An algorithmic method was developed to assess and replicate these interaction patterns in the artificial binding pockets built around small molecule conformers. It is shown that the integration of artificial binding pockets into the training process significantly enhanced the model's performance. Notably, PocketCFDM surpassed DiffDock in terms of non-bond interaction and steric clash numbers, and the inference speed. Future developments and optimizations of the model are discussed. The inference code and final model weights of PocketCFDM are accessible publicly via the GitHub repository: https://github.com/vtarasv/pocket-cfdm.git.

2.
Mol Inform ; 42(8-9): e2300006, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37293808

RESUMO

The new high selective mAChRs M3 inhibitors with IC50 in nanomolecular ranges, which can be the prototypes for effective COPD and asthma treatment drugs, were discovered with computational approaches among trifluoromethyl containing hexahydropyrimidinones/thiones. Compounds [6-(4-ethoxy-3-methoxy-phenyl)-4-hydroxy-2-thioxo-4-(trifluoromethyl)hexahydropyrimidin-5-yl]-phenyl-methanone (THPT-1) and 5-benzoyl-6-(3,4-dimethoxyphenyl)-4-hydroxy-4-(trifluoromethyl)hexahydropyrimidin-2-one (THPO-4) have been proved to be a highly effective (with IC50 values of 1.62 ⋅ 10-7  M and 3.09 ⋅ 10-9  M, respectively) at the same concentrations significantly competitive inhibit the signal conduction through mAChR3 in comparison with ipratropium bromide, without significant effect on mAChR2, nicotinic cholinergic and adrenergic receptors.


Assuntos
Broncodilatadores , Tionas , Broncodilatadores/farmacologia , Broncodilatadores/uso terapêutico , Ipratrópio/farmacologia , Ipratrópio/uso terapêutico , Acetilcolina , Desenho Assistido por Computador
3.
Struct Chem ; 34(3): 1157-1171, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36248344

RESUMO

Protein kinase Cß (PKCß) 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 PKCß 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 PKCß 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. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02075-y.

4.
Future Med Chem ; 14(17): 1223-1237, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35876255

RESUMO

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.


Assuntos
Aminoacil-tRNA Sintetases , Mycobacterium tuberculosis , Tuberculose , Acetamidas/uso terapêutico , Aminoacil-tRNA Sintetases/uso terapêutico , Humanos , Aprendizado de Máquina , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
5.
J Antibiot (Tokyo) ; 75(6): 321-332, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35440771

RESUMO

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 IC50 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 KD 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.


Assuntos
COVID-19 , Infecções Estafilocócicas , Aminoaciltransferases , Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Biofilmes , Cisteína Endopeptidases , Humanos , Testes de Sensibilidade Microbiana , RNA Viral/farmacologia , SARS-CoV-2 , Staphylococcus aureus
6.
Molecules ; 26(23)2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34885677

RESUMO

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.


Assuntos
Aminoaciltransferases/antagonistas & inibidores , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Aminoaciltransferases/genética , Antibacterianos/uso terapêutico , Proteínas de Bactérias/genética , Cisteína Endopeptidases/genética , Inibidores Enzimáticos/química , Humanos , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/enzimologia , Staphylococcus aureus/patogenicidade
7.
Sci Rep ; 11(1): 7162, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785838

RESUMO

Antibiotic resistance is a major problem of tuberculosis treatment. This provides the stimulus for the search of novel molecular targets and approaches to reduce or forestall resistance emergence in Mycobacterium tuberculosis. Earlier, we discovered a novel small-molecular inhibitor among 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazoles targeting simultaneously two enzymes-mycobacterial leucyl-tRNA synthetase (LeuRS) and methionyl-tRNA synthetase (MetRS), which are promising molecular targets for antibiotic development. Unfortunately, the identified inhibitor does not reveal antibacterial activity toward M. tuberculosis. This study aims to develop novel aminoacyl-tRNA synthetase inhibitors among this chemical class with antibacterial activity toward resistant strains of M. tuberculosis. We performed molecular docking of the library of 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazole derivatives and selected 41 compounds for investigation of their inhibitory activity toward MetRS and LeuRS in aminoacylation assay and antibacterial activity toward M. tuberculosis strains using microdilution assay. In vitro screening resulted in 10 compounds active against MetRS and 3 compounds active against LeuRS. Structure-related relationships (SAR) were established. The antibacterial screening revealed 4 compounds active toward M. tuberculosis mono-resistant strains in the range of concentrations 2-20 mg/L. Among these compounds, only one compound 27 has significant enzyme inhibitory activity toward mycobacterial MetRS (IC50 = 148.5 µM). The MIC for this compound toward M. tuberculosis H37Rv strain is 12.5 µM. This compound is not cytotoxic to human HEK293 and HepG2 cell lines. Therefore, 3-phenyl-5-(1-phenyl-1H-[1,2,3]triazol-4-yl)-[1,2,4]oxadiazole derivatives can be used for further chemical optimization and biological research to find non-toxic antituberculosis agents with a novel mechanism of action.


Assuntos
Aminoacil-tRNA Sintetases/antagonistas & inibidores , Antituberculosos/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Oxidiazóis/farmacologia , Tuberculose/tratamento farmacológico , Aminoacil-tRNA Sintetases/metabolismo , Antituberculosos/química , Antituberculosos/uso terapêutico , Proteínas de Ciclo Celular , Descoberta de Drogas , Farmacorresistência Bacteriana , Proteínas Fúngicas/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Oxidiazóis/química , Oxidiazóis/uso terapêutico , Tuberculose/microbiologia , Proteínas Supressoras de Tumor
8.
Future Microbiol ; 15: 869-879, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32662670

RESUMO

Background: A major focus of tuberculosis drug discovery is aimed at the development of novel antibiotics with activity against drug-resistant strains of Mycobacterium tuberculosis. Results: We have synthesized ten isoniazid derivatives and investigated for antibacterial activity toward M. tuberculosis H37Rv and isoniazid-resistant strain SRI 1369. It was revealed that only one compound, isonicotinic acid (1-methyl-1H-pyrrol-2-ylmethylene)-hydrazide (1), is active toward isoniazid-resistant strain with minimum inhibitory concentration value of 0.14 µM. This compound is not cytotoxic toward human liver cells (HepG2; IC50 >100 µM), demonstrates good permeability in Caco-2 cells. Accordingly to the results of plasma protein binding assay, unbound fraction of compound 1, which potentially exhibits pharmacologic effects, is 57.9%. Conclusion: Therefore, isonicotinic acid (1-methyl-1H-pyrrol-2-ylmethylene)-hydrazide is a promising compound for further preclinical studies.


Assuntos
Antituberculosos/antagonistas & inibidores , Antituberculosos/farmacologia , Isoniazida/análogos & derivados , Isoniazida/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Humanos , Ácidos Isonicotínicos/química , Macrófagos , Testes de Sensibilidade Microbiana , Tuberculose/tratamento farmacológico
9.
J Comput Aided Mol Des ; 33(11): 955-964, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31691918

RESUMO

Mycobacterium tuberculosis infection remains a major cause of global morbidity and mortality due to the increase of antibiotics resistance. Dual/multi-target drug discovery is a promising approach to overcome bacterial resistance. In this study, we built ligand-based pharmacophore models and performed pharmacophore screening in order to identify hit compounds targeting simultaneously two enzymes-M. tuberculosis leucyl-tRNA synthetase (LeuRS) and methionyl-tRNA synthetase (MetRS). In vitro aminoacylation assay revealed five compounds from different chemical classes inhibiting both enzymes. Among them the most active compound-3-(3-chloro-4-methoxy-phenyl)-5-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-3H-[1,2,3]triazol-4-ylamine (1) inhibits mycobacterial LeuRS and MetRS with IC50 values of 13 µM and 13.8 µM, respectively. Molecular modeling study indicated that compound 1 has similar binding mode with the active sites of both aminoacyl-tRNA synthetases and can be valuable compound for further chemical optimization in order to find promising antituberculosis agents.


Assuntos
Antituberculosos/farmacologia , Inibidores Enzimáticos/farmacologia , Leucina-tRNA Ligase/antagonistas & inibidores , Metionina tRNA Ligase/antagonistas & inibidores , Mycobacterium tuberculosis/enzimologia , Antituberculosos/química , Descoberta de Drogas , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
10.
J Antibiot (Tokyo) ; 72(4): 218-224, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30662064

RESUMO

In this article, we report a series of benzaldehyde thiosemicarbazone derivatives possessing high activity toward actively replicating Mycobacterium tuberculosis strain with minimum inhibitory concentration (MIC) values in the range from 0.14 to 2.2 µM. Among them, two compounds-2-(4-phenethoxybenzylidene)hydrazine-1-carbothioamide (13) and 2-(3-isopropoxybenzylidene)hydrazine-1-carbothioamide (20) also demonstrate submicromolar antimycobacterial activity against M. tuberculosis under hypoxia with MIC values of 0.68 and 0.74 µM, respectively. The activity of compounds 13 and 20 toward five investigated isoniazid-, rifampicin-, and fluoroquinolone-resistant M. tuberculosis isolates is similar to commercially available antituberculosis drugs. The compounds 13 and 20 possess good ADME properties and have low cytotoxicity toward human liver cells (HepG2). Therefore, 2-(4-phenethoxybenzylidene)hydrazine-1-carbothioamide (13) and 2-(3-isopropoxybenzylidene)hydrazine-1-carbothioamide (20) are valuable candidates for further preclinical studies.


Assuntos
Antituberculosos/farmacologia , Benzaldeídos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tiossemicarbazonas/farmacologia , Antituberculosos/síntese química , Antituberculosos/toxicidade , Benzaldeídos/síntese química , Benzaldeídos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/toxicidade
11.
Medchemcomm ; 10(12): 2161-2169, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32206244

RESUMO

Effective treatment of tuberculosis is challenged by the rapid development of Mycobacterium tuberculosis (Mtb) multidrug resistance that presumably could be overcome with novel multi-target drugs. Aminoacyl-tRNA synthetases (AARSs) are an essential part of protein biosynthesis machinery and attractive targets for drug discovery. Here, we experimentally verify a hypothesis of simultaneous targeting of structurally related AARSs by a single inhibitor. We previously identified a new class of mycobacterial leucyl-tRNA synthetase inhibitors, N-benzylidene-N'-thiazol-2-yl-hydrazines. Molecular docking of a library of novel N-benzylidene-N'-thiazol-2-yl-hydrazine derivatives into active sites of M. tuberculosis LeuRS (MtbLeuRS) and MetRS (MtbMetRS) resulted in a panel of the best ranking compounds, which were then evaluated for enzymatic potency. Screening data revealed 11 compounds active against MtbLeuRS and 28 compounds active against MtbMetRS. The hit compounds display dual inhibitory potency as demonstrated by IC50 values for both enzymes. Compound 3 is active against Mtb H37Rv cells in in vitro bioassays.

12.
Mol Divers ; 22(4): 991-998, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29845490

RESUMO

Identification of new small molecules inhibiting protein kinase CK2 is highly required for the study of this protein's functions in cell and for the further development of novel pharmaceuticals against a variety of disorders associated with CK2 activity. In this article, a virtual screening of a random small-molecule library was performed and 12 compounds were initially selected for biochemical tests toward CK2. Among them, the most active compound 1 ([Formula: see text]) belonged to dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-4-ones. The complex of this compound with CK2 was analyzed, and key ligand-enzyme interactions were determined. Then, a virtual screening of 231 dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-4-one derivatives was performed and 37 compounds were chosen for in vitro testing. It was found that 32 compounds inhibit CK2 with [Formula: see text] values from 2.5 to 7.5 [Formula: see text]. These results demonstrate that dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-4-one is a novel class of CK2 inhibitors.


Assuntos
Caseína Quinase II/antagonistas & inibidores , Desenho de Fármacos , Imidazóis/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Caseína Quinase II/química , Caseína Quinase II/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismo , Pirimidinas/metabolismo , Relação Estrutura-Atividade
13.
Pharmaceuticals (Basel) ; 10(1)2017 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-28085026

RESUMO

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.

14.
J Enzyme Inhib Med Chem ; 31(sup4): 160-169, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27590574

RESUMO

In this article, the derivatives of 3-quinoline carboxylic acid were studied as inhibitors of protein kinase CK2. Forty-three new compounds were synthesized. Among them 22 compounds inhibiting CK2 with IC50 in the range from 0.65 to 18.2 µM were identified. The most active inhibitors were found among tetrazolo-quinoline-4-carboxylic acid and 2-aminoquinoline-3-carboxylic acid derivatives.


Assuntos
Ácidos Carboxílicos/farmacologia , Caseína Quinase II/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Caseína Quinase II/metabolismo , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade
15.
J Enzyme Inhib Med Chem ; 31(sup2): 201-207, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27241561

RESUMO

The increase of antibiotic resistance amongst Mycobacterium tuberculosis strains has become one of the most pressing problems of modern medicine. Therefore, the search of antibiotics against M. tuberculosis with novel mechanisms of action is very important. We have identified inhibitors of M. tuberculosis leucyl-tRNA synthetase (LeuRS) among the derivatives of 5-phenylamino-2H-[1,2,4]triazin-3-one. The most active compounds 5-(5-chloro-2-hydroxy-phenylamino)-6-methyl-2H-[1,2,4]triazin-3-one and 5-(5-chloro-2-hydroxy-phenylamino)-2H-[1,2,4]triazin-3-one inhibit M. tuberculosis LeuRS with IC50 of 7.6 µÐœ and 7.2 µÐœ, respectively. It was established that the inhibitory activity of compounds against pathogenic LeuRS is 10-fold better, than for human enzyme.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Leucina-tRNA Ligase/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Triazinas/farmacologia , Antibacterianos/análise , Antibacterianos/isolamento & purificação , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Leucina-tRNA Ligase/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química
16.
Eur J Med Chem ; 115: 148-60, 2016 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-27017545

RESUMO

An extension of our previous research work has resulted in a number of new ATP-competitive CK2 inhibitors that have been identified among 4-aminothieno[2,3-d]pyrimidine derivatives. The most active compounds obtained in the course of the research are 3-(5-p-tolyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5e (NHTP23, IC50 = 0.01 µM), 3-(5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5g (NHTP25, IC50 = 0.065 µM) and 3-(6-methyl-5-phenyl-thieno[2,3-d]pyrimidin-4-ylamino)-benzoic acid, 5n (NHTP33, IC50 = 0.008 µM). Structure-activity relationships of the tested 4-aminothieno[2,3-d]pyrimidine derivatives have been studied and their binding mode with ATP-acceptor site of CK2 has been proposed. A negative effect of intramolecular hydrogen bonding in the compounds' structure is discussed.


Assuntos
Caseína Quinase II/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Caseína Quinase II/metabolismo , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
17.
Bioorg Med Chem ; 24(5): 1023-31, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26822568

RESUMO

Tuberculosis is a serious infectious disease caused by human pathogen bacteria Mycobacterium tuberculosis. Bacterial drug resistance is a very significant medical problem nowadays and development of novel antibiotics with different mechanisms of action is an important goal of modern medical science. Leucyl-tRNA synthetase (LeuRS) has been recently clinically validated as antimicrobial target. Here we report the discovery of small-molecule inhibitors of M. tuberculosis LeuRS. Using receptor-based virtual screening we have identified six inhibitors of M. tuberculosis LeuRS from two different chemical classes. The most active compound 4-{[4-(4-Bromo-phenyl)-thiazol-2-yl]hydrazonomethyl}-2-methoxy-6-nitro-phenol (1) inhibits LeuRS with IC50 of 6µM. A series of derivatives has been synthesized and evaluated in vitro toward M. tuberculosis LeuRS. It was revealed that the most active compound 2,6-Dibromo-4-{[4-(4-nitro-phenyl)-thiazol-2-yl]-hydrazonomethyl}-phenol inhibits LeuRS with IC50 of 2.27µM. All active compounds were tested for antimicrobial effect against M. tuberculosis H37Rv. The compound 1 seems to have the best cell permeability and inhibits growth of pathogenic bacteria with IC50=10.01µM and IC90=13.53µM.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Leucina-tRNA Ligase/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Tuberculose/tratamento farmacológico , Sequência de Aminoácidos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Leucina-tRNA Ligase/química , Leucina-tRNA Ligase/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Mycobacterium tuberculosis/química , Nitrofenóis/síntese química , Nitrofenóis/química , Nitrofenóis/farmacologia , Estrutura Terciária de Proteína , Alinhamento de Sequência , Tuberculose/microbiologia
18.
ACS Chem Biol ; 10(7): 1654-60, 2015 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-25961323

RESUMO

CK2 is a Ser/Thr kinase recruited by tumor cells to avoid cell death. 4'-Carboxy-6,8-dibromo-flavonol (FLC26) is a nanomolar CK2 inhibitor reducing the physiological phosphorylation of CK2 biomarkers and inducing cell death. Its binding mode to the ATP site was predicted to depend primarily on noncovalent interactions not comprising halogen bonds. We confirm this by two independent cocrystal structures which additionally show that FLC26 is selective for an open, protein kinase-untypical conformation of the hinge/helix αD region. The structures suggest how the bromo substituents, found previously in lead optimization studies, contribute to the inhibitory efficacy. In this context, one of the complex structures, obtained by crystallization with the kosmotropic salt NaCl, revealed an unconventional π-halogen bond between the 8-bromo substituent of FLC26 and an aromatic side chain which is absent under low-salt conditions. The kosmotropic salt sensitivity of π-halogen bonds is a novel feature which requires attention in structural comparisons and halogen-bond-based explanations.


Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Trifosfato de Adenosina/metabolismo , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/química , Caseína Quinase II/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Halogenação , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica , Estrutura Secundária de Proteína , Sais/química
19.
Bioorg Med Chem ; 23(10): 2489-97, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25882527

RESUMO

Apoptosis signal-regulating kinase 1 (ASK1) plays important roles in the pathogenesis of type 1 and type 2 diabetes, autoimmune disorders, cancer and neurodegenerative diseases suggesting that small compounds inhibiting ASK1 could be used for the treatment of these pathologies. We have identified novel chemical class of ASK1 inhibitors, namely benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one, using molecular modeling techniques. It was found that the most active compound 1-(6-fluoro-benzothiazol-2-yl)-3-hydroxy-5-[3-(3-methyl-butoxy)-phenyl]-4-(2-methyl-2,3-dihydro-benzofuran-5-carbonyl)-1,5-dihydro-pyrrol-2-one (BPyO-34) inhibits ASK1 with IC50 of 0.52µM in vitro in kinase assay. The structure-activity relationships of 34 derivatives of benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one have been studied and binding mode of this chemical class has been proposed.


Assuntos
MAP Quinase Quinase Quinase 5/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Pirróis/química , Bibliotecas de Moléculas Pequenas/química , Tiazóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação , Ensaios Enzimáticos , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , MAP Quinase Quinase Quinase 5/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Pirróis/síntese química , Proteínas Recombinantes , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-Atividade , Tiazóis/síntese química , Interface Usuário-Computador
20.
J Enzyme Inhib Med Chem ; 30(1): 126-32, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24939105

RESUMO

New class of FGFR1 kinase inhibitors with naphthostyril heterocycle has been identified. A series of N-phenylnaphthostyril-1-sulfonamides has been synthesized and tested in vitro. It was revealed that the most active compound N-(4-hydroxyphenyl)naphthostyril-1-sulfonamide inhibited FGFR1 with IC50 of 2 µM. In our preliminary studies, N-phenylnaphthostyril-1-sulfonamides demonstrated selectivity of FGFR1 inhibition and antiproliferative activity on cancer cell line. N-phenylnaphthostyril-1-sulfonamides have a good potential for further development as anticancer agents.


Assuntos
Antineoplásicos/síntese química , Quinolinas/síntese química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Estirenos/síntese química , Sulfonamidas/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Expressão Gênica , Humanos , Concentração Inibidora 50 , Quinolinas/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Estirenos/farmacologia , Sulfonamidas/farmacologia
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