RESUMO
The major cysteine protease of Trypanosoma cruzi, cruzain (CRZ), has been described as a therapeutic target for Chagas' disease, which affects millions of people worldwide. Thus, a series of CRZ inhibitors has been studied, including a new competitive inhibitor, Nequimed176 (NEQ176). Nevertheless, the structural and dynamic basis for CRZ inhibition remains unclear. Hoping to contribute to this ever-growing understanding of timescale dynamics in the CRZ inhibition mechanism, we have performed the first study using 100 ns of molecular dynamics (MD) simulations of two CRZ systems in an aqueous solvent under pH 5.5: CRZ in the apo form (ligand free) and CRZ complexed to NEQ176. According to the MD simulations, the enzyme adopts an open conformation in the apo form and a closed conformation in the NEQ176-CRZ complex. We also suggest that this closed conformation is related to the hydrogen-bonding interactions between NEQ176 and CRZ, which occurs through key residues, mainly Gly66, Met68, Asn69, and Leu160. In addition, the cross-correlation analysis shows evidence of the correlated motions among Ala110-Asp140, Leu160-Gly189, and Glu190-Gly215 subdomains, as well as, the movements related to Ala1-Thr59 and Asp60-Pro90 regions seem to be crucial for CRZ activity.
Assuntos
Cisteína Endopeptidases/química , Inibidores de Cisteína Proteinase/química , Simulação de Dinâmica Molecular , Proteínas de Protozoários/química , Solventes/química , Trypanosoma cruzi/enzimologia , Sítios de Ligação , Domínio Catalítico , Inibidores de Cisteína Proteinase/farmacologia , Ligação de Hidrogênio , Concentração de Íons de Hidrogênio , Modelos Moleculares , Conformação Molecular , Domínios e Motivos de Interação entre Proteínas , Proteínas de Protozoários/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
AIM: Platelets plays a central role in hemostatic processes and consequently are similarly involved in pathological processes, such as arterial thrombosis and atherosclerosis. Herein we described the synthesis, antiplatelet profile and structure-activity relationship (SAR) of a new series of N'-substitutedphenylmethylene-1H-pyrazolo[3,4-b]pyridine-carbohydrazide derivatives (3a-3k). METHODS: These compounds were synthesized in good yield and tested in platelet aggregation assays using collagen, ADP and arachidonic acid as agonists. We also performed a SAR studies using SPARTAN' 08 program, in silico ADMET screening and the Lipinski " rule of five " using Osiris Property Explorer and molinspiration on-line programs. RESULTS: Interestingly, the new compounds were active against collagen and arachidonic acid (AA) with the two most actives compounds (3a and 3c - IC(50)=61 microM and 68 microM respectively) almost 5-fold more potent than aspirin (IC(50)=300 microM). These derivatives showed low theoretical toxicity risks in in silico ADMET screening and fulfilled the Lipinski rule of five, suggesting good oral biodisponibility. CONCLUSION: This work showed carbohydrazide group as potential for designing new antiplatelets. On that purpose, 3a and 3c may act as prototypes to generate more efficient and safe molecules for treating thrombotic diseases.
Assuntos
Plaquetas/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Pirazóis/farmacologia , Piridinas/farmacologia , Trombose/tratamento farmacológico , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/química , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Trombose/patologiaRESUMO
Human Immunodeficiency Virus type 1 Reverse Transcriptase (HIV-1 RT) is one of the most important targets for treatment of Acquired Immune Deficiency Syndrome (AIDS). It catalyzes the reverse transcription of HIV-RNA into a double stranded DNA, and the knowledge of its substrate specificity and catalytic mechanism has guided the development of several inhibitors widely used on current HIV/AIDS therapy. However, mutations in HIV-1 RT structure can lead to the emergence of drug-resistant virus strains. The goal of this review is to summarize relevant structural features of HIV-1 RT and its inhibitors in such a way that this cost-effective target in the development of new antiretroviral drugs is particularly highlighted.
Assuntos
Transcriptase Reversa do HIV/efeitos dos fármacos , HIV-1/enzimologia , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/genética , HIV-1/genética , HIV-1/fisiologia , Humanos , Modelos Moleculares , Conformação Proteica , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Replicação ViralRESUMO
Hepatitis C, Dengue and West Nile virus are among of the most important flaviviruses that share one important serine protease enzyme. Serine proteases belong to the most studied class of proteolytic enzymes, and are a primary target in the drug development field. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N-t-Boc amino acid amides derived of isomannide as potential serine proteases inhibitors.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Flaviviridae/enzimologia , Peptídeos/química , Serina Endopeptidases/química , Inibidores de Serina Proteinase/química , Proteínas Virais/química , Animais , Infecções por Flaviviridae/tratamento farmacológico , Humanos , Estrutura Molecular , Proteínas Virais/antagonistas & inibidoresRESUMO
Hepatitis C, Dengue and West Nile virus are some of the most important flaviviruses, that share one important serine protease enzyme. Serine proteases are the most studied class of proteolytic enzyme and, in these cases, a primary target for drug discovery. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N- t-Boc amino acid esters derived of isomannide as potential serine proteases inhibitors.
Assuntos
Aminoácidos/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Inibidores Enzimáticos/farmacologia , Manitol/química , Serina Endopeptidases/química , Carbono/química , Vírus da Dengue/metabolismo , Flavivirus/metabolismo , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Manose/química , Modelos Químicos , Modelos Moleculares , Peptídeos/química , Conformação Proteica , Temperatura , Proteínas não Estruturais Virais/químicaRESUMO
The snake venom thrombin-like enzymes (SVTLEs) comprise a number of serine proteases functionally and structurally related to thrombin. Until recently, only nine complete sequences of this subgroup of the serine protease family were known. Over the past 5 years, the primary structure of several SVTLEs has been characterized, and now this family includes several members. Of particular interest is their possible use in pathologies such as thrombosis. The aim of the present review is to summarize the state of the art concerning the evolutionary, structural and biological features of the SVTLEs.
Assuntos
Batroxobina , Serina Endopeptidases , Venenos de Serpentes/química , Trombina , Sequência de Aminoácidos , Animais , Batroxobina/química , Batroxobina/classificação , Batroxobina/fisiologia , Batroxobina/uso terapêutico , Sítios de Ligação , Domínio Catalítico , Inibidores Enzimáticos/metabolismo , Hemostáticos/química , Hemostáticos/metabolismo , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Conformação Proteica , Alinhamento de Sequência , Serina Endopeptidases/química , Serina Endopeptidases/classificação , Serina Endopeptidases/fisiologia , Serina Endopeptidases/uso terapêutico , Trombina/química , Trombina/genética , Trombina/metabolismoRESUMO
Com o objetivo de aumentar a irrigaçäo sanguínea cerebral e do membro superior direito, foi rrealizada uma derivaçäo fêmoro-axilar direita em uma paciente portadora de oclusöes e estenoses dos ramos supra-aórticos outras doenças associadas que näo permitiam a toracotomia. Embora os resultados näo tenham sido plenamente satisfatórios, este procedimento mostrou-se hemodinamicamente viável e uma alternativa válida para o tratamento da insuficiência vascular cerebral e de membros superiores, em casos eecíficos.