RESUMO
Two series of peptidomimetics were designed, prepared and evaluated for their anti-HCV activity. One series possesses a C-terminal carboxylate functionality. In the other series, the electrophilic vinyl sulfonate moiety was introduced as a novel class of HCV NS3/4A protease inhibitors. In vitro based studies were then performed to evaluate the efficacies of the inhibitors using Human hepatoma cells, with the vinyl sulfonate ester (10) in particular, found to have highly potent anti-HCV activity with an EC(50) = 0.296 µM. Finally, molecular modeling studies were performed through docking of the synthesized compounds in the HCV NS3/4A protease active site to assess their binding modes with the enzyme and gain further insight into their structure-activity relationships.
Assuntos
Antivirais/química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Inibidores de Serina Proteinase/química , Antivirais/síntese química , Desenho de Fármacos , Hepacivirus/enzimologia , Humanos , Modelos Moleculares , Peptidomiméticos/síntese química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-AtividadeRESUMO
New 2-(3,4,5-triacetoxybenzoylamino)benzothiazoles (4a~5f) and 2-(galloylamino)benzothiazoles (6a~7f), were designed as topoisomerase-I inhibitors. Compare/fit studies between these molecules and the generated topoisomerase-I inhibitors hypothesis revealed that 4a~5f have higher fitting values than (6a~7f). Also, docking of 4a~7f with the topoisomerase-I enzyme prioritized the higher activity of (4a~5f) than (6a~7f). These molecules were synthesized and biologically evaluated for their in vitro cytotoxic activity against Hela and MCF7 human cancer cell lines in comparison to Camptothecin (topo-I inhibitor) and doxorubicin (topo-II inhibitors) as reference drugs. Such screening revealed that compounds 4d, 4e, 4h, 5b, 5c and 5e have comparable higher cytotoxic activity in both cultures than these reference drugs. The highest active molecule was 5f that gave 1.5 folds higher cytotoxic activity against Hela cell cultures and 1.9 folds higher activity against MCF7 cell lines than doxorubicin and 1.6 folds and 2.2 folds higher activity towards the two respective cultures than Camptothecin.
Assuntos
DNA Topoisomerases Tipo I/metabolismo , Desenho de Fármacos , Tiazóis/farmacologia , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/toxicidade , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Células Tumorais CultivadasRESUMO
This work presents the first structure-based activity prediction model for benzothiadiazines against various genotypes of HCV NS5b polymerase (1a, 1b and 4).The model is a comprehensive workflow of structure-based field template followed by guided docking. The field template was used as a pre-filter and a tool to provide hits in good orientation and position. It was created based on detailed molecular interaction field analysis which includes Topomer CoMFA, grid independent analysis and Superstar. On the other hand, Guided docking was used as a refinement and assessment tool. It was actively directed by two scores: Moldock score as an interaction descriptor (r(2)=0.65) and a template similarity score as a measure for accurate binding-mode compliance. The docking template was based on energy-based pharmacophore analysis. The whole procedure was formulated and tweaked for both screening (ROC of AUC=0.91) and activity prediction (r(2) of 0.8) for the genotype 1a. In order to widen the model scope, linear interaction energy was used as a tool for predicting activities of other genotypes based on the docked ligand poses while mutation binding energy was used to investigate the effect of each amino acid mutation in genotype 4. The model was applied for structure-based fragment hopping by screening a library designed by reaction enumeration. A top scoring hit was used to generate a focused library such that it has lower TPSA than the original class ligands and thus better pharmacokinetic properties. After that, experimental validation was carried out by the synthesis of this library and its biological evaluation which yielded compounds that exhibit EC(50) ranging from 1.86 to 23 µM.
Assuntos
Benzotiadiazinas/química , Inibidores Enzimáticos/química , Hepacivirus/enzimologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Benzotiadiazinas/síntese química , Benzotiadiazinas/farmacologia , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Genótipo , Simulação de Dinâmica Molecular , Mutação , Estrutura Terciária de Proteína , Relação Quantitativa Estrutura-Atividade , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
A series of new 3-mercapto-2-methyl-propanoyl-pyrrolidine derivatives (V, VIa-e) were designed. A new validated ACE inhibitors pharmacophore model (hypothesis) was generated for the first time in this research from the biologically active (frozen) conformation of Lisinopril-Human ACE complex that was downloaded from PDB, using stepwise technique of CATALYST modules. The molecular modeling compare-fit study of the designed molecules (V, VIa-e), with such ACE inhibitors hypothesis was fulfilled, and several compounds showed significant high simulation fit values. The compounds with high fit values were synthesized and biologically evaluated in vivo as hypotensive agents. It appears that the in vivo hypotensive activity of compounds V, VIa, VIb, and VIe was consistent with their molecular modeling results, and compound VIe showed the highest activity in comparison to Captopril.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , Propionatos/química , Pirrolidinas/química , Inibidores da Enzima Conversora de Angiotensina/síntese química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacologia , Catálise , Gatos , Simulação por Computador , Bases de Dados de Proteínas , Desenho de Fármacos , Modelos Químicos , Modelos Moleculares , Propionatos/síntese química , Propionatos/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of novel quinazolin-4-ones was designed and their molecular modeling simulation fitting to a new HipHop 3D pharmacophore model using CATALYST was examined. Several compounds showed significant high simulation fit values. The designed compounds were synthesized and eight of them were biologically evaluated in vitro using an AT1 receptor binding assay, where compound XX competed weakly against radiolabeled Sar1Ile8-angiotensin II (Ang II) binding, compounds XIV and XXII showed moderate competition, and compound XXV showed almost equal ability to displace radiolabeled Sar1Ile8-Ang II binding to AT1 receptors as losartan. In vivo biological evaluation study of compounds XIV, XXII, and XXV on both normotensive and hypertensive rats revealed that compound XXV demonstrated higher hypotensive and antihypertensive activity than the reference compound losartan. To obtain a highly active compound from a candidate set of only eight tested compounds illustrates the power and utility of our pharmacophore model.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Anti-Hipertensivos/síntese química , Compostos de Bifenilo/síntese química , Quinazolinas/síntese química , Tetrazóis/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Ligação Competitiva , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Células CHO , Cricetinae , Cricetulus , Desenho de Fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Modelos Moleculares , Quinazolinas/química , Quinazolinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacologiaRESUMO
A series of thiazolone derivatives was designed and synthesized as potential HCV NS5B allosteric polymerase inhibitors at the allosteric site thumb II. Their antiviral activity was evaluated and molecular modeling was utilized to give further envision on their probable binding modes in the allosteric binding site. Among the tested molecules, compound 9b displayed sub-micromolar inhibitory activity with an EC50 of 0.79 µM indicating excellent potency profile. It also showed good safety profile (CC50≥75 µM and SI≥94.3).
Assuntos
Antivirais , Desenho de Fármacos , Hepacivirus/efeitos dos fármacos , Tiazóis/química , Sítio Alostérico , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Sítios de Ligação , Modelos Moleculares , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/farmacologia , Proteínas não Estruturais Virais/efeitos dos fármacosRESUMO
First structure-based activity prediction model of topologically diverse inhibitors of Palm I allosteric site of HCV NS5b polymerase enzyme is reported here. The model is a workflow of structure-based pharmacophore followed by guided docking. The pharmacophore was constructed using a novel procedure which includes PLIF (protein ligand interaction fingerprint), Hypogen, contact-based pharmacophore and shape constraints. The guided docking was tweaked using both a scoring function of high correlation with activity (ChemPLP) and essential pharmacophore features. Statistically, ROC analysis for the workflow, deploying the novel technique of virtual decoys, yielded AUC of 0.947. Experimentally, the model was used to screen Asinex GOLD database yielding a new hit with a different scaffold which was further confirmed by synthesis and biological evaluation.
Assuntos
Antivirais/química , Hepacivirus/química , Simulação de Acoplamento Molecular , Interface Usuário-Computador , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Sítio Alostérico , Área Sob a Curva , Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Curva ROC , Eletricidade Estática , Relação Estrutura-Atividade , TermodinâmicaRESUMO
A series of new imidazo[5,1-b]quinazoline derivatives (VII-IX) was designed, synthesized, and biologically evaluated for their in vivo hypotensive or hypertensive activities. The design of these compounds was based upon the molecular modeling simulation of the fitting values and conformational energy values of the best-fitted conformers to both the alpha(1)-adrenoceptor (alpha(1)-AR) agonist and alpha(1)-adrenoceptor (alpha(1)-AR) antagonist hypotheses. These hypotheses were generated from their corresponding lead compounds using CATALYST software. The simulation studies predicted that compounds IXa and IXe would have probable affinity for the alpha(1)-AR antagonist hypothesis, while compounds IXb, IXc, and IXg predicted a higher affinity for the alpha(1)-AR agonist hypothesis. In vivo biological evaluation of these compounds for their effects on the blood pressure of normotensive cats was consistent with the results of molecular modeling studies, where compounds IXa and IXe exhibited hypotensive activity, while compounds IXb, IXc, and IXg resulted in increasing the blood pressure of the experimental animals at different doses.