Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 51.860
Filtrar
1.
Molecules ; 26(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669720

RESUMEN

Coronavirus desease 2019 (COVID-19) is responsible for more than 1.80 M deaths worldwide. A Quantitative Structure-Activity Relationships (QSAR) model is developed based on experimental pIC50 values reported for a structurally diverse dataset. A robust model with only five descriptors is found, with values of R2 = 0.897, Q2LOO = 0.854, and Q2ext = 0.876 and complying with all the parameters established in the validation Tropsha's test. The analysis of the applicability domain (AD) reveals coverage of about 90% for the external test set. Docking and molecular dynamic analysis are performed on the three most relevant biological targets for SARS-CoV-2: main protease, papain-like protease, and RNA-dependent RNA polymerase. A screening of the DrugBank database is executed, predicting the pIC50 value of 6664 drugs, which are IN the AD of the model (coverage = 79%). Fifty-seven possible potent anti-COVID-19 candidates with pIC50 values > 6.6 are identified, and based on a pharmacophore modelling analysis, four compounds of this set can be suggested as potent candidates to be potential inhibitors of SARS-CoV-2. Finally, the biological activity of the compounds was related to the frontier molecular orbitals shapes.


Asunto(s)
Antivirales/química , Inhibidores de Cisteína Proteinasa/química , Bases de Datos de Compuestos Químicos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , /enzimología , Antivirales/uso terapéutico , /antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/uso terapéutico , Evaluación Preclínica de Medicamentos , Relación Estructura-Actividad Cuantitativa , /química
2.
Molecules ; 26(4)2021 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-33672721

RESUMEN

The ongoing coronavirus pandemic has been a burden on the worldwide population, with mass fatalities and devastating socioeconomic consequences. It has particularly drawn attention to the lack of approved small-molecule drugs to inhibit SARS coronaviruses. Importantly, lessons learned from the SARS outbreak of 2002-2004, caused by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), can be applied to current drug discovery ventures. SARS-CoV-1 and SARS-CoV-2 both possess two cysteine proteases, the main protease (Mpro) and the papain-like protease (PLpro), which play a significant role in facilitating viral replication, and are important drug targets. The non-covalent inhibitor, GRL-0617, which was found to inhibit replication of SARS-CoV-1, and more recently SARS-CoV-2, is the only PLpro inhibitor co-crystallised with the recently solved SARS-CoV-2 PLpro crystal structure. Therefore, the GRL-0617 structural template and pharmacophore features are instrumental in the design and development of more potent PLpro inhibitors. In this work, we conducted scaffold hopping using GRL-0617 as a reference to screen over 339,000 ligands in the chemical space using the ChemDiv, MayBridge, and Enamine screening libraries. Twenty-four distinct scaffolds with structural and electrostatic similarity to GRL-0617 were obtained. These proceeded to molecular docking against PLpro using the AutoDock tools. Of two compounds that showed the most favourable predicted binding affinities to the target site, as well as comparable protein-ligand interactions to GRL-0617, one was chosen for further analogue-based work. Twenty-seven analogues of this compound were further docked against the PLpro, which resulted in two additional hits with promising docking profiles. Our in silico pipeline consisted of an integrative four-step approach: (1) ligand-based virtual screening (scaffold-hopping), (2) molecular docking, (3) an analogue search, and, (4) evaluation of scaffold drug-likeness, to identify promising scaffolds and eliminate those with undesirable properties. Overall, we present four novel, and lipophilic, scaffolds obtained from an exhaustive search of diverse and uncharted regions of chemical space, which may be further explored in vitro through structure-activity relationship (SAR) studies in the search for more potent inhibitors. Furthermore, these scaffolds were predicted to have fewer off-target interactions than GRL-0617. Lastly, to our knowledge, this work contains the largest ligand-based virtual screen performed against GRL-0617.


Asunto(s)
Antivirales/química , Inhibidores de Cisteína Proteinasa/química , Simulación del Acoplamiento Molecular , /enzimología , Antivirales/uso terapéutico , /antagonistas & inhibidores , Cristalografía por Rayos X , Inhibidores de Cisteína Proteinasa/uso terapéutico , Evaluación Preclínica de Medicamentos , Humanos
3.
Sci Rep ; 11(1): 6248, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33737523

RESUMEN

The outbreak of a novel febrile respiratory disease called COVID-19, caused by a newfound coronavirus SARS-CoV-2, has brought a worldwide attention. Prioritizing approved drugs is critical for quick clinical trials against COVID-19. In this study, we first manually curated three Virus-Drug Association (VDA) datasets. By incorporating VDAs with the similarity between drugs and that between viruses, we constructed a heterogeneous Virus-Drug network. A novel Random Walk with Restart method (VDA-RWR) was then developed to identify possible VDAs related to SARS-CoV-2. We compared VDA-RWR with three state-of-the-art association prediction models based on fivefold cross-validations (CVs) on viruses, drugs and virus-drug associations on three datasets. VDA-RWR obtained the best AUCs for the three fivefold CVs, significantly outperforming other methods. We found two small molecules coming together on the three datasets, that is, remdesivir and ribavirin. These two chemical agents have higher molecular binding energies of - 7.0 kcal/mol and - 6.59 kcal/mol with the domain bound structure of the human receptor angiotensin converting enzyme 2 (ACE2) and the SARS-CoV-2 spike protein, respectively. Interestingly, for the first time, experimental results suggested that navitoclax could be potentially applied to stop SARS-CoV-2 and remains to further validation.


Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/química , Ribavirina/química , Glicoproteína de la Espiga del Coronavirus/química , Adenosina Monofosfato/química , Alanina/química , Compuestos de Anilina/química , Evaluación Preclínica de Medicamentos , Genoma Viral , Simulación del Acoplamiento Molecular , Sulfonamidas/química
4.
Sci Rep ; 11(1): 6397, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33737545

RESUMEN

A new and more aggressive strain of coronavirus, known as SARS-CoV-2, which is highly contagious, has rapidly spread across the planet within a short period of time. Due to its high transmission rate and the significant time-space between infection and manifestation of symptoms, the WHO recently declared this a pandemic. Because of the exponentially growing number of new cases of both infections and deaths, development of new therapeutic options to help fight this pandemic is urgently needed. The target molecules of this study were the nitro derivatives of quinoline and quinoline N-oxide. Computational design at the DFT level, docking studies, and molecular dynamics methods as a well-reasoned strategy will aid in elucidating the fundamental physicochemical properties and molecular functions of a diversity of compounds, directly accelerating the process of discovering new drugs. In this study, we discovered isomers based on the nitro derivatives of quinoline and quinoline N-oxide, which are biologically active compounds and may be low-cost alternatives for the treatment of infections induced by SARS-CoV-2.


Asunto(s)
Quinolinas/química , /química , /tratamiento farmacológico , Simulación por Computador , Teoría Funcional de la Densidad , Evaluación Preclínica de Medicamentos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Quinolinas/uso terapéutico
5.
Zhongguo Zhong Yao Za Zhi ; 46(2): 320-332, 2021 Jan.
Artículo en Chino | MEDLINE | ID: mdl-33645118

RESUMEN

With the increasing incidence of hepatobiliary diseases, it is particularly important to understand the role of molecular, cellular and physiological factors in the clinical diagnosis and treatment with traditional Chinese medicine(TCM) in the development of liver disease. Appropriate animal models can help us identify the possible mechanisms of relevant diseases. Danio rerio(zebrafish) model was traditionally used to study embryonic development, and has been gradually used in screening and evaluation of liver diseases and relevant drug in recent years. Zebrafish embryos develop rapidly and the digestive organs of 5-day-old juvenile fish are all mature. At this stage, they may develop hepatobiliary diseases induced by developmental defects or compounds. Zebrafish liver is similar to human liver in cell composition, function, signal transduction, response to injury and cell process mediating liver disease. Furthermore, due to the high conservation of genes and proteins between humans and zebrafish, zebrafish becomes an alternative system for studying basic mechanisms of liver disease. Therefore, genetic screening could be performed to identify new genes involving specific disease processes, and chemical screening could be made for drugs in specific processes. This paper briefly introduced the experimental properties of zebrafish as model system, emphasized the study progress of zebrafish models for pathological mechanism of liver diseases, especially fatty liver, and drug screening and evaluation, so as to provide ideas and techniques for the future liver toxicity assessment of TCM.


Asunto(s)
Hepatopatías , Pez Cebra , Animales , Evaluación Preclínica de Medicamentos , Humanos , Hígado , Hepatopatías/genética , Medicina China Tradicional , Pez Cebra/genética
7.
Molecules ; 26(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669763

RESUMEN

Computer aided drug-design methods proved to be powerful tools for the identification of new therapeutic agents. We employed a structure-based workflow to identify new inhibitors targeting mTOR kinase at rapamycin binding site. By combining molecular dynamics (MD) simulation and pharmacophore modelling, a simplified structure-based pharmacophore hypothesis was built starting from the FKBP12-rapamycin-FRB ternary complex retrieved from RCSB Protein Data Bank (PDB code 1FAP). Then, the obtained model was used as filter to screen the ZINC biogenic compounds library, containing molecules derived from natural sources or natural-inspired compounds. The resulting hits were clustered according to their similarity; moreover, compounds showing the highest pharmacophore fit-score were chosen from each cluster. The selected molecules were subjected to docking studies to clarify their putative binding mode. The binding free energy of the obtained complexes was calculated by MM/GBSA method and the hits characterized by the lowest ΔGbind values were identified as potential mTOR inhibitors. Furthermore, the stability of the resulting complexes was studied by means of MD simulation which revealed that the selected compounds were able to form a stable ternary complex with FKBP12 and FRB domain, thus underlining their potential ability to inhibit mTOR with a rapamycin-like mechanism.


Asunto(s)
Simulación por Computador , Inhibidores de Proteínas Quinasas/farmacología , Sirolimus/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Sitios de Unión , Evaluación Preclínica de Medicamentos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Dominios Proteicos , Proteína 1A de Unión a Tacrolimus/química , Proteína 1A de Unión a Tacrolimus/metabolismo , Interfaz Usuario-Computador
8.
PLoS One ; 16(3): e0248348, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33690649

RESUMEN

Pseudoviruses are useful surrogates for highly pathogenic viruses because of their safety, genetic stability, and scalability for screening assays. Many different pseudovirus platforms exist, each with different advantages and limitations. Here we report our efforts to optimize and characterize an HIV-based lentiviral pseudovirus assay for screening neutralizing antibodies for SARS-CoV-2 using a stable 293T cell line expressing human angiotensin converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We assessed different target cells, established conditions that generate readouts over at least a two-log range, and confirmed consistent neutralization titers over a range of pseudovirus input. Using reference sera and plasma panels, we evaluated assay precision and showed that our neutralization titers correlate well with results reported in other assays. Overall, our lentiviral assay is relatively simple, scalable, and suitable for a variety of SARS-CoV-2 entry and neutralization screening assays.


Asunto(s)
/metabolismo , Lentivirus/metabolismo , Pruebas de Neutralización/métodos , /genética , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Evaluación Preclínica de Medicamentos/métodos , Células HEK293 , Humanos , /patogenicidad , Glicoproteína de la Espiga del Coronavirus/genética
9.
Molecules ; 26(4)2021 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-33671801

RESUMEN

Several derivatives containing morpholine/piperidine, anilines, and dipeptides as pending moieties were prepared using s-triazine as a scaffold. These compounds were evaluated for their anticancer activity against two human breast cancer cell lines (MCF-7 and MDA-MB-231), a colon cancer cell line (HCT-116), and a non-tumorigenic cell line (HEK 293). Tamoxifen was used as a reference. Animal toxicity tests were carried out in zebrafish embryos. Most of these compounds showed a higher activity against breast cancer than colon cancer. Compound 3a-which contains morpholine, aniline, and glycylglycinate methyl ester-showed a high level of cytotoxicity against MCF-7 cells with IC50 values of less than 1 µM. This compound showed a much lower level of toxicity against the non-tumorigenic HEK-293 cell line, and in the in vivo studies using zebrafish embryos. Furthermore, it induced cell cycle arrest at the G2/M phase, and apoptosis in MCF-7 cells. On the basis of our results, 3a emerges as a potential candidate for further development as a therapeutic drug to treat hormone receptor-positive breast cancer.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Dipéptidos/farmacología , Triazinas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Dipéptidos/síntesis química , Dipéptidos/química , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Triazinas/síntesis química , Triazinas/química , Pez Cebra/embriología
10.
Aging (Albany NY) ; 13(5): 6258-6272, 2021 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-33678621

RESUMEN

It has been confirmed that the new coronavirus SARS-CoV-2 caused the global pandemic of coronavirus disease 2019 (COVID-19). Studies have found that 3-chymotrypsin-like protease (3CLpro) is an essential enzyme for virus replication, and could be used as a potential target to inhibit SARS-CoV-2. In this work, 3CLpro was used as the target to complete the high-throughput virtual screening of the FDA-approved drugs, and Indinavir and other 10 drugs with high docking scores for 3CLpro were obtained. Studies on the binding pattern of 3CLpro and Indinavir found that Indinavir could form the stable hydrogen bond (H-bond) interactions with the catalytic dyad residues His41-Cys145. Binding free energy study found that Indinavir had high binding affinity with 3CLpro. Subsequently, molecular dynamics simulations were performed on the 3CLpro and 3CLpro-Indinavir systems, respectively. The post-dynamic analyses showed that the conformational state of the 3CLpro-Indinavir system transformed significantly and the system tended to be more stable. Moreover, analyses of the residue interaction network (RIN) and H-bond occupancy revealed that the residue-residue interaction at the catalytic site of 3CLpro was significantly enhanced after binding with Indinavir, which in turn inactivated the protein. In short, through this research, we hope to provide more valuable clues against COVID-19.


Asunto(s)
/tratamiento farmacológico , /enzimología , /farmacología , /virología , /metabolismo , Aprobación de Drogas , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Indinavir/química , Indinavir/farmacología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , /efectos de los fármacos , /química
11.
AAPS PharmSciTech ; 22(3): 84, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33649887

RESUMEN

Prediction of performance of traditional, reformulated, and novel oral formulations in adults and pediatrics is of great importance. This study was conducted to assess solubility of celecoxib in age-appropriate fasted- and fed-state gastric and intestinal biorelevant media, classify celecoxib into biopharmaceutical classification system (BCS), and assess the effects of age-related developmental changes in the composition and volume of gastrointestinal fluids on the solubility and performance of oral formulations containing celecoxib. Solubility of celecoxib was assessed at 37°C in the pH range specified by the BCS-based criteria in 13 age-appropriate biorelevant media reflective of the gastric and proximal small intestinal environment in both fasted and fed states in adults and different pediatric subpopulations. A validated HPLC-UV method was used to quantify celecoxib. Experimental and computational molecular descriptors and in vivo pharmacokinetic data were used to assign the permeability class of celecoxib. Celecoxib belonged to BCS class 2. The pediatric to adult solubility ratios were outside the 80-125% boundaries in 3 and borderline in 1 biorelevant media. Significant age-related variability could be predicted for oral formulations containing celecoxib intended for pediatric use. Findings of this study indicated that the criteria used in the adult BCS might not be directly applied to pediatric subpopulations.


Asunto(s)
Productos Biológicos/clasificación , Productos Biológicos/farmacocinética , Celecoxib/clasificación , Celecoxib/farmacocinética , Ayuno/metabolismo , Absorción Gastrointestinal/fisiología , Administración Oral , Adulto , Antiinflamatorios no Esteroideos/clasificación , Antiinflamatorios no Esteroideos/farmacocinética , Líquidos Corporales/química , Líquidos Corporales/metabolismo , Niño , Preescolar , Evaluación Preclínica de Medicamentos/métodos , Predicción , Absorción Gastrointestinal/efectos de los fármacos , Humanos , Lactante , Recién Nacido , Permeabilidad , Solubilidad
12.
AAPS PharmSciTech ; 22(3): 105, 2021 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-33718988

RESUMEN

Medicine regulators require the melting points for crystalline drugs, as they are a test for chemical and physical quality. Many drugs, especially salt-forms, suffer concomitant degradation during melting; thus, it would be useful to know if the endotherm associated with melt degradation may be used for characterising the crystallinity of a powder blend. Therefore, the aim of this study was to investigate whether melt-degradation transitions can detect amorphous content in a blend of crystalline and amorphous salbutamol sulphate. Salbutamol sulphate was rendered amorphous by freeze and spray-drying and blended with crystalline drug, forming standards with a range of amorphous content. Crystalline salbutamol sulphate was observed to have a melt-degradation onset of 198.2±0.2°C, while anhydrous amorphous salbutamol sulphate prepared by either method showed similar glass transition temperatures of 119.4±0.7°C combined. Without the energy barrier provided by the ordered crystal lattice, the degradation endotherm for amorphous salbutamol sulphate occurred 50°C below the melting point, with an onset of 143.6±0.2°C. The enthalpies for this degradation transition showed no significant difference between freeze- and spray-dried samples (p>0.05). Distinct from convention, partial integration of the crystalline melt-degradation endotherm was applied to the region 193-221°C which had no contribution from the degradation of amorphous salbutamol sulphate. The linear correlation of these partial areas with amorphous content, R2=0.994, yielded limits of detection and quantification of 0.13% and 0.44% respectively, independent of drying technique. Melt-degradation transitions may be re-purposed for the measurement of amorphous content in powder blends, and they have potential for evaluating disorder more generally.


Asunto(s)
Albuterol/síntesis química , Albuterol/farmacocinética , Química Farmacéutica/métodos , Broncodilatadores/síntesis química , Broncodilatadores/farmacocinética , Rastreo Diferencial de Calorimetría/métodos , Cristalización/métodos , Composición de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/métodos , Polvos , Temperatura de Transición
13.
Database (Oxford) ; 20212021 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-33787872

RESUMEN

Understanding the underlying molecular and structural similarities between seemingly heterogeneous sets of drugs can aid in identifying drug repurposing opportunities and assist in the discovery of novel properties of preclinical small molecules. A wealth of information about drug and small molecule structure, targets, indications and side effects; induced gene expression signatures; and other attributes are publicly available through web-based tools, databases and repositories. By processing, abstracting and aggregating information from these resources into drug set libraries, knowledge about novel properties of drugs and small molecules can be systematically imputed with machine learning. In addition, drug set libraries can be used as the underlying database for drug set enrichment analysis. Here, we present Drugmonizome, a database with a search engine for querying annotated sets of drugs and small molecules for performing drug set enrichment analysis. Utilizing the data within Drugmonizome, we also developed Drugmonizome-ML. Drugmonizome-ML enables users to construct customized machine learning pipelines using the drug set libraries from Drugmonizome. To demonstrate the utility of Drugmonizome, drug sets from 12 independent SARS-CoV-2 in vitro screens were subjected to consensus enrichment analysis. Despite the low overlap among these 12 independent in vitro screens, we identified common biological processes critical for blocking viral replication. To demonstrate Drugmonizome-ML, we constructed a machine learning pipeline to predict whether approved and preclinical drugs may induce peripheral neuropathy as a potential side effect. Overall, the Drugmonizome and Drugmonizome-ML resources provide rich and diverse knowledge about drugs and small molecules for direct systems pharmacology applications. Database URL: https://maayanlab.cloud/drugmonizome/.


Asunto(s)
/tratamiento farmacológico , Bases de Datos Farmacéuticas , /efectos de los fármacos , Antivirales/química , Antivirales/farmacología , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Reposicionamiento de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Técnicas In Vitro , Aprendizaje Automático , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Bibliotecas de Moléculas Pequeñas , Interfaz Usuario-Computador , Replicación Viral/efectos de los fármacos
14.
Biomolecules ; 11(2)2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33557097

RESUMEN

The COVID-19 pandemic has already taken the lives of more than 2 million people worldwide, causing several political and socio-economic disturbances in our daily life. At the time of publication, there are non-effective pharmacological treatments, and vaccine distribution represents an important challenge for all countries. In this sense, research for novel molecules becomes essential to develop treatments against the SARS-CoV-2 virus. In this context, Mexican natural products have proven to be quite useful for drug development; therefore, in the present study, we perform an in silico screening of 100 compounds isolated from the most commonly used Mexican plants, against the SARS-CoV-2 virus. As results, we identify ten compounds that meet leadlikeness criteria (emodin anthrone, kaempferol, quercetin, aesculin, cichoriin, luteolin, matricin, riolozatrione, monocaffeoyl tartaric acid, aucubin). According to the docking analysis, only three compounds target the key proteins of SARS-CoV-2 (quercetin, riolozatrione and cichoriin), but only one appears to be safe (cichoriin). ADME (absorption, distribution, metabolism and excretion) properties and the physiologically based pharmacokinetic (PBPK) model show that cichoriin reaches higher lung levels (100 mg/Kg, IV); therefore, it may be considered in developing therapeutic tools.


Asunto(s)
Productos Biológicos/análisis , Productos Biológicos/uso terapéutico , /virología , Simulación por Computador , Evaluación Preclínica de Medicamentos , Medicina de Hierbas , Medicina Tradicional , /fisiología , Productos Biológicos/química , Productos Biológicos/farmacología , Quimioinformática , Humanos , Simulación del Acoplamiento Molecular , /efectos de los fármacos
15.
Viruses ; 13(2)2021 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-33572659

RESUMEN

Rift valley fever virus (RVFV) is a mosquito-borne virus endemic to sub-Saharan African countries, and the first sporadic outbreaks outside Africa were reported in the Asia-Pacific region. There are no approved therapeutic agents available for RVFV; however, finding an effective antiviral agent against RVFV is important. This study aimed to evaluate the antiviral, antioxidant and anti-inflammatory activity of medicinal plant extracts. Twenty medicinal plants were screened for their anti-RVFV activity using the cytopathic effect (CPE) reduction method. The cytotoxicity assessment of the extracts was done before antiviral screening using the MTT assay. Antioxidant and reactive oxygen/nitrogen species' (ROS/RNS) inhibitory activity by the extracts was investigated using non-cell-based and cell-based assays. Out of twenty plant extracts tested, eight showed significant potency against RVFV indicated by a decrease in tissue culture infectious dose (TCID50) < 105. The cytotoxicity of extracts showed inhibitory concentrations values (IC50) > 200 µg/mL for most of the extracts. The antioxidant activity and anti-inflammatory results revealed that extracts scavenged free radicals exhibiting an IC50 range of 4.12-20.41 µg/mL and suppressed the production of pro-inflammatory mediators by 60-80% in Vero cells. This study demonstrated the ability of the extracts to lower RVFV viral load and their potency to reduce free radicals.


Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Antivirales/farmacología , Extractos Vegetales/farmacología , Plantas Medicinales/química , Virus de la Fiebre del Valle del Rift/efectos de los fármacos , Animales , Antiinflamatorios/química , Antioxidantes/química , Antivirales/química , Chlorocebus aethiops , Evaluación Preclínica de Medicamentos , Extractos Vegetales/química , Fiebre del Valle del Rift/tratamiento farmacológico , Fiebre del Valle del Rift/virología , Virus de la Fiebre del Valle del Rift/crecimiento & desarrollo , Sudáfrica , Células Vero
17.
PLoS One ; 16(2): e0245962, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33524017

RESUMEN

Effective SARS-CoV-2 antiviral drugs are desperately needed. The SARS-CoV-2 main protease (Mpro) appears as an attractive target for drug development. We show that the existing pharmacopeia contains many drugs with potential for therapeutic repurposing as selective and potent inhibitors of SARS-CoV-2 Mpro. We screened a collection of ~6,070 drugs with a previous history of use in humans for compounds that inhibit the activity of Mpro in vitro and found ~50 compounds with activity against Mpro. Subsequent dose validation studies demonstrated 8 dose responsive hits with an IC50 ≤ 50 µM. Hits from our screen are enriched with hepatitis C NS3/4A protease targeting drugs including boceprevir, ciluprevir. narlaprevir, and telaprevir. This work suggests previous large-scale commercial drug development initiatives targeting hepatitis C NS3/4A viral protease should be revisited because some previous lead compounds may be more potent against SARS-CoV-2 Mpro than boceprevir and suitable for rapid repurposing.


Asunto(s)
Antivirales/farmacología , Antivirales/uso terapéutico , Evaluación Preclínica de Medicamentos , Reposicionamiento de Medicamentos , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Inhibidores de Proteasas/farmacología , /efectos de los fármacos , Bioensayo , Fluorescencia , Ensayos Analíticos de Alto Rendimiento , Humanos , Reproducibilidad de los Resultados
18.
Int J Mol Sci ; 22(3)2021 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-33530458

RESUMEN

A high-throughput drug screen identifies potentially promising therapeutics for clinical trials. However, limitations that persist in current disease modeling with limited physiological relevancy of human patients skew drug responses, hamper translation of clinical efficacy, and contribute to high clinical attritions. The emergence of induced pluripotent stem cell (iPSC) technology revolutionizes the paradigm of drug discovery. In particular, iPSC-based three-dimensional (3D) tissue engineering that appears as a promising vehicle of in vitro disease modeling provides more sophisticated tissue architectures and micro-environmental cues than a traditional two-dimensional (2D) culture. Here we discuss 3D based organoids/spheroids that construct the advanced modeling with evolved structural complexity, which propels drug discovery by exhibiting more human specific and diverse pathologies that are not perceived in 2D or animal models. We will then focus on various central nerve system (CNS) disease modeling using human iPSCs, leading to uncovering disease pathogenesis that guides the development of therapeutic strategies. Finally, we will address new opportunities of iPSC-assisted drug discovery with multi-disciplinary approaches from bioengineering to Omics technology. Despite technological challenges, iPSC-derived cytoarchitectures through interactions of diverse cell types mimic patients' CNS and serve as a platform for therapeutic development and personalized precision medicine.


Asunto(s)
Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Descubrimiento de Drogas/métodos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Ingeniería de Tejidos/métodos , Animales , /patología , Enfermedades del Sistema Nervioso Central/patología , Descubrimiento de Drogas/instrumentación , Evaluación Preclínica de Medicamentos/instrumentación , Evaluación Preclínica de Medicamentos/métodos , Humanos , Células Madre Pluripotentes Inducidas/patología , Dispositivos Laboratorio en un Chip , Organoides/citología , Organoides/efectos de los fármacos , Organoides/patología , Ingeniería de Tejidos/instrumentación , Infección por el Virus Zika/tratamiento farmacológico , Infección por el Virus Zika/patología
19.
Microb Pathog ; 152: 104762, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33524563

RESUMEN

Till date millions of people are infected by SARS-CoV-2 throughout the world, while no potential therapeutics or vaccines are available to combat this deadly virus. Blocking of human angiotensin-converting enzyme 2 (ACE-2) receptor, the binding site of SARS-CoV-2 spike protein, an effective strategy to discover a drug for COVID-19. Herein we have selected 24 anti-bacterial and anti-viral drugs and made a comprehensive analysis by screened them virtually against ACE-2 receptor to find the best blocker by molecular docking and molecular dynamics studies. Analysis of results revealed that, Cefpiramide (CPM) showed the highest binding affinity of -9.1 kcal/mol. Furthermore, MD study for 10 ns and evaluation of parameters like RMSD, RMSF, radius of gyration, solvent accessible surface area analysis confirmed that CPM effectively binds and blocks ACE-2 receptor efficiently.


Asunto(s)
Bloqueadores del Receptor Tipo 2 de Angiotensina II/uso terapéutico , Antivirales/uso terapéutico , Evaluación Preclínica de Medicamentos/métodos , /efectos de los fármacos , Bloqueadores del Receptor Tipo 2 de Angiotensina II/química , Antivirales/química , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular
20.
Biochem Biophys Res Commun ; 545: 203-207, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33571909

RESUMEN

The current COVID-19 pandemic requires urgent development of effective therapeutics. 5-amino levulinic acid (5-ALA) is a naturally synthesized amino acid and has been used for multiple purposes including as an anticancer therapy and as a dietary supplement due to its high bioavailability. In this study, we demonstrated that 5-ALA treatment potently inhibited infection of SARS-CoV-2, a causative agent of COVID-19, in cell culture. The antiviral effects could be detected in both human and non-human cells, without significant cytotoxicity. Therefore, 5-ALA is worth to be further investigated as an antiviral drug candidate for COVID-19.


Asunto(s)
Antivirales/farmacología , Ácidos Levulínicos/farmacología , Animales , Antivirales/administración & dosificación , /virología , Células CACO-2 , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Compuestos Ferrosos/farmacología , Humanos , Ácidos Levulínicos/administración & dosificación , Células Vero
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...