RESUMO
This study investigated the potential of selected compounds as inhibitors of SARS-CoV-2 Mpro through pharmacokinetic and toxicological analyses, molecular docking, and molecular dynamics simulations. In silico molecular docking simulations revealed promising ligands with favorable binding affinities for Mpro, ranging from -6.2 to -9.5 kcal/mol. Moreover, molecular dynamics simulations demonstrated the stability of protein-ligand complexes over 200 ns, maintaining protein secondary structures. MM-PBSA analysis revealed favorable interactions between ligands and Mpro, with negative binding energy values. Hydrogen bond formation capacity during molecular dynamics was confirmed, indicating consistent interactions with Mpro catalytic residues. Based on these findings, selected ligands show promise for future studies in developing COVID-19 treatments.
Assuntos
Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , SARS-CoV-2 , SARS-CoV-2/efeitos dos fármacos , Humanos , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/metabolismo , Antivirais/química , Antivirais/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ligação de Hidrogênio , Ligantes , COVID-19/virologia , Ligação ProteicaRESUMO
Aedes aegypti mosquitoes transmit several human pathogens that cause millions of deaths worldwide, mainly in Latin America. The indiscriminate use of insecticides has resulted in the development of species resistance to some such compounds. Piperidine, a natural alkaloid isolated from Piper nigrum, has been used as a hit compound due to its larvicidal activity against Aedes aegypti. In the present study, piperidine derivatives were studied through in silico methods: pharmacophoric evaluation (PharmaGist), pharmacophoric virtual screening (Pharmit), ADME/Tox prediction (Preadmet/Derek 10.0®), docking calculations (AutoDock 4.2) and molecular dynamics (MD) simulation on GROMACS-5.1.4. MP-416 and MP-073 molecules exhibiting ΔG binding (MMPBSA -265.95 ± 1.32 kJ/mol and -124.412 ± 1.08 kJ/mol, respectively) and comparable to holo (ΔG binding = -216.21 ± 0.97) and pyriproxyfen (a well-known larvicidal, ΔG binding= -435.95 ± 2.06 kJ/mol). Considering future in vivo assays, we elaborated the theoretical synthetic route and made predictions of the synthetic accessibility (SA) (SwissADME), lipophilicity and water solubility (SwissADME) of the promising compounds identified in the present study. Our in silico results show that MP-416 and MP-073 molecules could be potent insecticides against the Aedes aegypti mosquitoes.
Assuntos
Aedes , Inseticidas , Animais , Biologia Computacional , Humanos , Inseticidas/farmacologia , Hormônios Juvenis , Larva , Piperidinas/farmacologia , Extratos Vegetais/farmacologiaRESUMO
The present work describes the acetylcholinesterase inhibitory activity of Ocotea pomaderroides extracts besides the chemical composition of chromatographic fractions. The hexane, dichloromethane and ethyl acetate extract soluble fractions showed high Electrophorus electricus acetylcholinesterase (EelAChE) inhibition (92.18, 71.86 and 74.25%, respectively) while the butanolic and aqueous extracts showed moderate to low activities (44.48 and 20.74%, respectively). The high-performance liquid chromatography coupled with electrospray ionization multiple-stage mass spectrometry (HPLC-ESI-MSn) analysis led to the identification of the alkaloids and flavonol glycoside derivatives present in these extracts. The binding profile of the alkaloids and their atomic effect on 3D structure of Electrophorus electricus AchE (EelAChE) were assessed with molecular modeling.
Assuntos
Inibidores da Colinesterase/farmacologia , Ocotea , Extratos Vegetais , Acetilcolinesterase/metabolismo , Cromatografia Líquida de Alta Pressão , Ocotea/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em TandemRESUMO
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has received global attention due to the serious threat it poses to public health. Since the outbreak in December 2019, millions of people have been affected and its rapid global spread has led to an upsurge in the search for treatment. To discover hit compounds that can be used alone or in combination with repositioned drugs, we first analyzed the pharmacokinetic and toxicological properties of natural products from Brazil's semiarid region. After, we analyzed the site prediction and druggability of the SARS-CoV-2 main protease (Mpro), followed by docking and molecular dynamics simulation. The best SARS-CoV-2 Mpro complexes revealed that other sites were accessed, confirming that our approach could be employed as a suitable starting protocol for ligand prioritization, reinforcing the importance of catalytic cysteine-histidine residues and providing new structural data that could increase the antiviral development mainly against SARS-CoV-2. Here, we selected 10 molecules that could be in vitro assayed in response to COVID-19. Two compounds (b01 and b02) suggest a better potential for interaction with SARS-CoV-2 Mpro and could be further studied.
Assuntos
Produtos Biológicos/farmacologia , Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/efeitos dos fármacos , Desenho de Fármacos , SARS-CoV-2/química , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Antivirais/farmacologia , Sítios de Ligação , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Conformação Proteica , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/efeitos dos fármacosRESUMO
Tetragonisca angustula honey was fractioned in a SiO2 column to furnish three fractions (A-C) in which four hydroxycinnamic acid-Spermidine amides (HCAAs), known as N', Nâ³, Nâ´-tris-p-coumaroyl spermidine, N', Nâ³-dicaffeoyl, Nâ´-coumaroyl spermidine, N', Nâ³, Nâ´-tris-caffeoyl spermidine and N', Nâ³-dicaffeoyl and Nâ´-feruloyl spermidine were identified in the fractions B and C by electrospray ionization tandem mass spectrometry. A primary culture model previously infected with Neospora caninum (72 h) was used to evaluate the honey fractions (A-C) for two-time intervals: 24 and 72 h. Parasitic reduction ranged from 38% on fraction C (12.5 µg/ml), after 24 h, to 54% and 41% with fractions B and C (25 µg/ml) after 72 h of treatment, respectively. Additionally, HCAAs did not show any cell toxicity for 24 and 72 h. For infected cultures (72 h), the active fractions B (12.5 µg/ml) and C (25 µg/ml) decreased their NO content. In silico studies suggest that HCAAs may affect the parasite's redox pathway and improve the oxidative effect of NO released from infected cells. Here, we presented for the first time, that HCAAs from T. angustula honey have the potential to inhibit the growth of N. caninum protozoa.
Assuntos
Antiprotozoários/farmacologia , Abelhas , Mel , Neospora/efeitos dos fármacos , Espermidina/química , Amidas/química , Animais , Antiprotozoários/química , Brasil , Células Cultivadas , Coccidiose/tratamento farmacológico , Simulação por Computador , Ácidos Cumáricos/química , NADH NADPH Oxirredutases/antagonistas & inibidores , Neuroglia/efeitos dos fármacos , Neuroglia/parasitologia , Óxido Nítrico/metabolismo , Ratos Wistar , Espermidina/análiseRESUMO
Among the neglected tropical diseases, leishmaniasis stands out for its worldwide distribution and diversity of symptoms. Cutaneous leishmaniasis (CL), for instance, is endemic in 18 countries, but the available drugs to fight it have high toxicity and low patient adherence. In order to overcome this, dilemma drugs that target enzymes which are absent in the human host, such as Leishmania braziliensis sterol C24-methyltransferase (SMT-C24, EC 2.1.1.41), are needed. However, medicinal chemistry efforts toward this goal have been hampered by the low yield of soluble recombinant SMT-C24 afforded by currently available expression systems. Herein, we show that a combination of molecular biology and chromatographic strategies may increase the yield of LbSMT-C24 in up to fivefold. These results lay the ground for future investigation of this enzyme as a drug target.
Assuntos
Escherichia coli/crescimento & desenvolvimento , Leishmania braziliensis/enzimologia , Metiltransferases/genética , Clonagem Molecular , Escherichia coli/genética , Leishmania braziliensis/genética , Metiltransferases/metabolismo , Engenharia de Proteínas , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Proteínas Recombinantes/metabolismoRESUMO
Leishmaniasis, a neglected tropical disease, is a major cause of morbidity and mortality worldwide. Of the three main clinical forms, cutaneous leishmaniasis (CL) is the most common and 40 million people are at risk in the endemic areas. Currently, the available drugs to fight leishmaniasis have high toxicity and poor efficiency. Then, it is very important to search for effective and safe drugs that would target essential enzymes from the parasite, such as lanosterol 14-alpha demethylase (CYP51, EC 1.14.13.70) from Leishmania braziliensis. Because most drug design efforts have been directed for Leishmania non-braziliensis species, there is no structural or kinetic data regarding L. braziliensis CYP51. Herein, we present for the first time molecular biology efforts and purification protocol to obtain the enzyme LbCYP51. These results lay the ground for future investigation of drugs against this target.
Assuntos
Leishmania braziliensis/genética , Esterol 14-Desmetilase/genética , Esterol 14-Desmetilase/metabolismo , Animais , Humanos , Lanosterol/genética , Lanosterol/metabolismo , Leishmania/genética , Leishmania/metabolismo , Leishmaniose/genéticaRESUMO
Mortality is high in patients with acute coronary failure and cardiogenic shock. The most commonly used device for hemodynamic support is the intra-aortic balloon, which, however, may be insufficient in patients with refractory cardiogenic shock. This is a case report of a patient complaining of two days of intense and oppressive chest pain, radiating to the left arm. The ECG showed ST elevation. The patient was submitted to angioplasty and stent implant in the anterior descending artery and developed cardiogenic shock refractory to vasoactive drugs and intra-aortic balloon. Hemodynamic measures were carried out and we chose to use an Impella 2.5 device, by percutaneous route, for circulatory support.
Assuntos
Balão Intra-Aórtico , Choque Cardiogênico/cirurgia , Idoso , Angioplastia Coronária com Balão , Feminino , Hemodinâmica/fisiologia , Humanos , Infarto do Miocárdio/cirurgia , Choque Cardiogênico/etiologia , Stents , Resultado do TratamentoRESUMO
Em pacientes com insuficiência coronariana aguda e choque cardiogênico, a mortalidade é alta. O dispositivo mais utilizado para suporte hemodinâmico é o balão intra-aórtico que, no entanto, pode ser insuficiente em pacientes com choque cardiogênico refratário. Relato de caso com dois dias de dor precordial opressiva e intensa, irradiada para membro superior esquerdo. ECG com supradesnivelamento anterior. Realizado angioplastia e implante de stent na artéria descendente anterior. Evolução com choque cardiogênico refratário ao uso de drogas vasoativas e balão intra-aórtico. Foram realizadas medidas hemodinâmicas e decidiu-se pela colocação do Impella® 2,5 por via percutânea para assistência circulatória.
Mortality is high in patients with acute coronary failure and cardiogenic shock. The most commonly used device for hemodynamic support is the intra-aortic balloon, which, however, may be insufficient in patients with refractory cardiogenic shock. This is a case report of a patient complaining of two days of intense and oppressive chest pain, radiating to the left arm. The ECG showed ST elevation. The patient was submitted to angioplasty and stent implant in the anterior descending artery and developed cardiogenic shock refractory to vasoactive drugs and intra-aortic balloon. Hemodynamic measures were carried out and we chose to use an Impella 2.5 device, by percutaneous route, for circulatory support.
Assuntos
Idoso , Feminino , Humanos , Balão Intra-Aórtico , Choque Cardiogênico/cirurgia , Angioplastia Coronária com Balão , Hemodinâmica/fisiologia , Infarto do Miocárdio/cirurgia , Stents , Choque Cardiogênico/etiologia , Resultado do TratamentoRESUMO
A 35-year-old patient was seen in an Emergency Department. with six hours of pain in the right iliac fossa and fever. The hypothesis diagnosis was acute appendicitis and an exploring laparotomy for appendectomy was carried out. The patient returned to the hospital three days after having been discharged. debilitated. feverish. having alterations in speech. reduction in the level of consciousness and complete hemiparesis to the left. The computed tomography scan of the skull and the liquor puncture were normal. Cerebral magnetic resonance image showed aspects compatible with vertebrobasilar ischemic stroke. Transesphofagic echocardiogram showed vegetation of the aortic valve and moderate aortic insufficiency. Blood cultures were positive for Enterococcus bovis.
Assuntos
Abdome Agudo/etiologia , Endocardite/complicações , Doenças das Valvas Cardíacas/complicações , Insuficiência Vertebrobasilar/etiologia , Adulto , Valva Aórtica , Apendicite/diagnóstico , Endocardite/microbiologia , Enterococcus/isolamento & purificação , Doenças das Valvas Cardíacas/microbiologia , Humanos , Masculino , Paresia/etiologia , Insuficiência Vertebrobasilar/diagnósticoRESUMO
Paciente de 35 anos de idade foi atendido em Serviço de Emergência com seis horas de dor em fossa ilíaca direita e febre. Feita hipótese diagnóstica de apendicite aguda e realizada laparotomia exploradora. com apendicectomia. O paciente retornou ao hospital três dias após alta hospitalar. prostrado. febril. com alteração de fala. diminuição de nível de consciência e com hemiparesia completa à esquerda. CT scan de crânio e punção de líquor normal. RMN de encéfalo revelou aspectos compatíveis com AVC isquêmico vertebro-basilar. Ecocardiograma transesofágico demonstrou vegetação em valva aórtica e insuficiência aórtica moderada e hemoculturas foram positivas para Enterococcus bovis.
A 35-year-old patient was seen in an Emergency Department. with six hours of pain in the right iliac fossa and fever. The hypothesis diagnosis was acute appendicitis and an exploring laparotomy for appendectomy was carried out. The patient returned to the hospital three days after having been discharged. debilitated. feverish. having alterations in speech. reduction in the level of consciousness and complete hemiparesis to the left. The computed tomography scan of the skull and the liquor puncture were normal. Cerebral magnetic resonance image showed aspects compatible with vertebrobasilar ischemic stroke. Transesphofagic echocardiogram showed vegetation of the aortic valve and moderate aortic insufficiency. Blood cultures were positive for Enterococcus bovis.
Assuntos
Adulto , Humanos , Masculino , Abdome Agudo/etiologia , Endocardite/complicações , Doenças das Valvas Cardíacas/complicações , Insuficiência Vertebrobasilar/etiologia , Valva Aórtica , Apendicite/diagnóstico , Endocardite/microbiologia , Enterococcus/isolamento & purificação , Doenças das Valvas Cardíacas/microbiologia , Paresia/etiologia , Insuficiência Vertebrobasilar/diagnósticoRESUMO
BACKGROUND: Few studies evaluated prognostic factors of outpatients with heart failure of different etiologies including Chagas' heart disease. METHODS: We studied 1220 outpatients with heart failure in functional classes III and IV (NYHA) to evaluate prognostic factors. Patients aged 13-72 years (mean 45.5, standard deviation 11); 952 men (78%) and 268 women (22%) were followed up for 25.6+/-26 months from 1991 to 2000. Heart failure was attributed to idiopathic dilated cardiomyopathy in 454 (37%) patients. Etiologies were Chagas' heart disease in 242 (20%) patients, ischemic cardiomyopathy in 212 (17%), hypertensive cardiomyopathy in 170 (14%) and others in 142 (12%). Statistical analyses were performed with Kaplan-Meier and Cox proportional hazards methods, following a strategy of noninvasive model as well as in an invasive model to identify the risk of death. RESULTS: Four hundred fifteen (34%) patients died in the follow-up period, 71 (6%) patients underwent heart transplantation and 28 (2%) underwent other surgical interventions. In the noninvasive model, Chagas' heart disease (relative risk compared with other etiologies 2.26 to 2.97), left ventricular end diastolic diameter on echocardiography (relative risk 1.13) and left ventricular ejection fraction on radionuclide angiography (relative risk 0.96) were associated with higher mortality. In the invasive model, Chagas' heart disease (relative risk compared with other etiologies 2.66 to 9.13) was the most important determinant of mortality in association with the cardiac index (relative risk 0.40). CONCLUSIONS: In this cohort of patients with heart failure of different etiologies, Chagas' heart disease was the main prognostic factor for mortality.
Assuntos
Cardiomiopatia Chagásica/complicações , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/mortalidade , Registros Hospitalares , Pacientes Ambulatoriais , Medição de Risco , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Cateterismo Cardíaco , Cardiomiopatia Chagásica/diagnóstico , Cardiomiopatia Chagásica/mortalidade , Ecocardiografia Doppler , Eletrocardiografia Ambulatorial , Feminino , Seguimentos , Insuficiência Cardíaca/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Ventriculografia com Radionuclídeos , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendênciasRESUMO
A endomiocardiofibrose é uma doença comum em países tropicais, particularmente Uganda e Nigéria, e pode acometer tanto o ventrículo esquerdo como direito, gerando uma insuficiência cardíaca restritiva que, além dos sintomas clássicos, manifesta-se por ascite desproporcional ao edema periférico. Apresentamos o caso de uma portadora de endomiocardiofibrose refratária ao tratamento clínico, submetida ao tratamento cirúrgico com melhora clínica por curto período, voltando a apresentar sintomas incapacitantes três meses após a cirurgia de ressecção de fibrose endomiocárdica e plastia tricúspide. A paciente foi então submetida a transplante cardíaco ortotópico bicaval, com boa evolução clínica. É o primeiro caso de transplante cardíaco nesta doença, mostrando-se uma alternativa de tratamento promissora.
Assuntos
Feminino , Humanos , Pessoa de Meia-Idade , Fibrose Endomiocárdica/cirurgia , Transplante de Coração , Resultado do TratamentoRESUMO
OBJECTIVES: We hypothesized that exercise-related periodic breathing (EPB) would be associated with poor prognosis in advanced chronic heart failure (CHF). BACKGROUND: Patients with CHF might present instability of the ventilatory control system characterized by cyclic waxing and waning of tidal volume (periodic breathing [PB]). This condition is associated with several deleterious circulatory and neuro-endocrine responses; in fact, PB in awake and asleep patients has been identified as an independent risk factor for cardiac death. During exercise, however, the prognostic value of PB is still unknown in CHF patients awaiting heart transplantation. METHODS: Eighty-four patients with established CHF (65 male, 19 female) were submitted to clinical evaluation, echocardiogram, ventricular scintigraphy, determination of resting serum norepinephrine levels, and an incremental cardiopulmonary exercise test on cycle ergometer. Patients were followed for up to 49.7 months (median = 15.3), and 26 patients (30.9%) died during this period. RESULTS: Twenty-five of 84 patients presented EPB (29.7%). The following variables were related to mortality according to Kaplan-Meier and univariate Cox regression analysis: EPB (p = 0.004), New York Heart Association class (p = 0.04), serum norepinephrine (p = 0.06), peak oxygen uptake (ml.min(-1).kg(-1) and % predicted; p = 0.085 and p = 0.10, respectively), slope of the ratio of change in minute ventilation to change in carbon dioxide output during exercise (p = 0.10), and scintigraphic left ventricular ejection fraction (p = 0.10). Cox multivariate analysis identified EPB as the only independent variable for cardiac death prediction (p = 0.007). Therefore, EPB alone was associated with a 2.97-fold increase in risk of death in this population (95% confidence interval = 1.34 to 6.54). CONCLUSIONS: Exercise-related periodic breathing independently predicts cardiac mortality in CHF patients considered for heart transplantation.