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1.
Comput Biol Med ; 122: 103848, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32658735

RESUMEN

The recent outbreak of coronavirus disease-19 (COVID-19) continues to drastically affect healthcare throughout the world. To date, no approved treatment regimen or vaccine is available to effectively attenuate or prevent the infection. Therefore, collective and multidisciplinary efforts are needed to identify new therapeutics or to explore effectiveness of existing drugs and drug-like small molecules against SARS-CoV-2 for lead identification and repurposing prospects. This study addresses the identification of small molecules that specifically bind to any of the three essential proteins (RdRp, 3CL-protease and helicase) of SARS-CoV-2. By applying computational approaches we screened a library of 4574 compounds also containing FDA-approved drugs against these viral proteins. Shortlisted hits from initial screening were subjected to iterative docking with the respective proteins. Ranking score on the basis of binding energy, clustering score, shape complementarity and functional significance of the binding pocket was applied to identify the binding compounds. Finally, to minimize chances of false positives, we performed docking of the identified molecules with 100 irrelevant proteins of diverse classes thereby ruling out the non-specific binding. Three FDA-approved drugs showed binding to 3CL-protease either at the catalytic pocket or at an allosteric site related to functionally important dimer formation. A drug-like molecule showed binding to RdRp in its catalytic pocket blocking the key catalytic residues. Two other drug-like molecules showed specific interactions with helicase at a key domain involved in catalysis. This study provides lead drugs or drug-like molecules for further in vitro and clinical investigation for drug repurposing and new drug development prospects.


Asunto(s)
Betacoronavirus/enzimología , Infecciones por Coronavirus/tratamiento farmacológico , Reposicionamiento de Medicamentos , Neumonía Viral/tratamiento farmacológico , Inhibidores de Proteasas/farmacología , Dominio Catalítico , Simulación por Computador , Dimerización , Diseño de Fármacos , Humanos , Simulación del Acoplamiento Molecular , Pandemias , Inhibidores de Proteasas/química , Quinoxalinas/farmacología , Rimantadina/farmacología , Proteínas Virales/química
2.
Nat Commun ; 11(1): 3518, 2020 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-32665542

RESUMEN

Coronavirus Disease-2019 (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus. Various studies exist about the molecular mechanisms of viral infection. However, such information is spread across many publications and it is very time-consuming to integrate, and exploit. We develop CoVex, an interactive online platform for SARS-CoV-2 host interactome exploration and drug (target) identification. CoVex integrates virus-human protein interactions, human protein-protein interactions, and drug-target interactions. It allows visual exploration of the virus-host interactome and implements systems medicine algorithms for network-based prediction of drug candidates. Thus, CoVex is a resource to understand molecular mechanisms of pathogenicity and to prioritize candidate therapeutics. We investigate recent hypotheses on a systems biology level to explore mechanistic virus life cycle drivers, and to extract drug repurposing candidates. CoVex renders COVID-19 drug research systems-medicine-ready by giving the scientific community direct access to network medicine algorithms. It is available at https://exbio.wzw.tum.de/covex/.


Asunto(s)
Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Reposicionamiento de Medicamentos/métodos , Interacciones Microbiota-Huesped/fisiología , Neumonía Viral/tratamiento farmacológico , Algoritmos , Simulación por Computador , Humanos , Internet , Pandemias , Mapas de Interacción de Proteínas , Acoplamiento Viral/efectos de los fármacos
3.
Drug Discov Ther ; 14(3): 109-116, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32669519

RESUMEN

With the emergence of coronavirus disease 2019 (COVID-19) in late December 2019, many clinical studies on a group of the pre-existing medications have been conducted to treat this disease. The purpose of this review was to compile the clinical evidences on the use of the pre-existing medications and potential therapeutic options for the management of COVID-19. We reviewed the literature to highlight the clinical studies on the use of these medications to be available as a scientific overview for further perspectives. Inadequate clinical evidences are available to be affirmed for the repurposing of old medications, and large scale clinical studies are needed to be carried out to further confirm the use of these agents. The clinical use of these medications should be well explained and follow the framework of Monitored Emergency use of Unregistered Interventions (MEURI) of World Health Organization (WHO).


Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/administración & dosificación , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Reposicionamiento de Medicamentos/métodos , Hidroxicloroquina/administración & dosificación , Neumonía Viral/tratamiento farmacológico , Adenosina Monofosfato/administración & dosificación , Alanina/administración & dosificación , Antirreumáticos/administración & dosificación , Betacoronavirus/metabolismo , Ensayos Clínicos como Asunto/métodos , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/diagnóstico , Reposicionamiento de Medicamentos/tendencias , Humanos , Pandemias , Neumonía Viral/sangre , Neumonía Viral/diagnóstico
4.
J Transl Med ; 18(1): 278, 2020 07 09.
Artículo en Inglés | MEDLINE | ID: mdl-32646487

RESUMEN

BACKGROUND: Severe acute respiratory syndrome (SARS) has been initiating pandemics since the beginning of the century. In December 2019, the world was hit again by a devastating SARS episode that has so far infected almost four million individuals worldwide, with over 200,000 fatalities having already occurred by mid-April 2020, and the infection rate continues to grow exponentially. SARS coronavirus 2 (SARS-CoV-2) is a single stranded RNA pathogen which is characterised by a high mutation rate. It is vital to explore the mutagenic capability of the viral genome that enables SARS-CoV-2 to rapidly jump from one host immunity to another and adapt to the genetic pool of local populations. METHODS: For this study, we analysed 2301 complete viral sequences reported from SARS-CoV-2 infected patients. SARS-CoV-2 host genomes were collected from The Global Initiative on Sharing All Influenza Data (GISAID) database containing 9 genomes from pangolin-CoV origin and 3 genomes from bat-CoV origin, Wuhan SARS-CoV2 reference genome was collected from GeneBank database. The Multiple sequence alignment tool, Clustal Omega was used for genomic sequence alignment. The viral replicating enzyme, 3-chymotrypsin-like cysteine protease (3CLpro) that plays a key role in its pathogenicity was used to assess its affinity with pharmacological inhibitors and repurposed drugs such as anti-viral flavones, biflavanoids, anti-malarial drugs and vitamin supplements. RESULTS: Our results demonstrate that bat-CoV shares > 96% similar identity, while pangolin-CoV shares 85.98% identity with Wuhan SARS-CoV-2 genome. This in-depth analysis has identified 12 novel recurrent mutations in South American and African viral genomes out of which 3 were unique in South America, 4 unique in Africa and 5 were present in-patient isolates from both populations. Using state of the art in silico approaches, this study further investigates the interaction of repurposed drugs with the SARS-CoV-2 3CLpro enzyme, which regulates viral replication machinery. CONCLUSIONS: Overall, this study provides insights into the evolving mutations, with implications to understand viral pathogenicity and possible new strategies for repurposing compounds to combat the nCovid-19 pandemic.


Asunto(s)
Betacoronavirus/enzimología , Simulación por Computador , Infecciones por Coronavirus/virología , Cisteína Endopeptidasas/metabolismo , Replicación del ADN , Reposicionamiento de Medicamentos , Geografía , Neumonía Viral/virología , Proteínas no Estructurales Virales/metabolismo , Betacoronavirus/genética , Evolución Molecular , Genoma Viral , Humanos , Simulación del Acoplamiento Molecular , Mutación/genética , Tasa de Mutación , Pandemias , Filogenia , Ensamble de Virus
5.
J Biosci ; 452020.
Artículo en Inglés | MEDLINE | ID: mdl-32661214

RESUMEN

The current global pandemic COVID-19 caused by the SARS-CoV-2 virus has already inflicted insurmountable damage both to the human lives and global economy. There is an immediate need for identification of effective drugs to contain the disastrous virus outbreak. Global efforts are already underway at a war footing to identify the best drug combination to address the disease. In this review, an attempt has been made to understand the SARS-CoV-2 life cycle, and based on this information potential druggable targets against SARS-CoV-2 are summarized. Also, the strategies for ongoing and future drug discovery against the SARSCoV- 2 virus are outlined. Given the urgency to find a definitive cure, ongoing drug repurposing efforts being carried out by various organizations are also described. The unprecedented crisis requires extraordinary efforts from the scientific community to effectively address the issue and prevent further loss of human lives and health.


Asunto(s)
Corticoesteroides/uso terapéutico , Antivirales/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Reposicionamiento de Medicamentos , Factores Inmunológicos/uso terapéutico , Pandemias , Neumonía Viral/tratamiento farmacológico , Betacoronavirus/efectos de los fármacos , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Progresión de la Enfermedad , Descubrimiento de Drogas , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Hidroxicloroquina/uso terapéutico , Simulación del Acoplamiento Molecular , Terapia Molecular Dirigida/métodos , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/inmunología , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Neumonía Viral/virología , Transducción de Señal/genética , Transducción de Señal/inmunología , Glicoproteína de la Espiga del Coronavirus/antagonistas & inhibidores , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología
6.
Recenti Prog Med ; 111(7): 398-401, 2020.
Artículo en Italiano | MEDLINE | ID: mdl-32658877

RESUMEN

The SARS-CoV-2 pandemic has lifted the veil about how medical knowledge is produced and disseminated. Action Bias, together with economic, academic and media-related interests, has concurred to generate and spread low-value and even unreliable information about some hypothetical therapeutic interventions for CoViD-19. Not only this "infodemic" has weakened people's ability to make informed health choices, but it also has influenced the process of new evidence generation through the violation of the equipoise principle. The CoViD-19 infodemic has further highlighted the need for reliable health information and for people to enter the process of understanding and promoting valuable research. Through a randomized controlled trial, the Informed Health Choices project has shown that it is not impossible neither quixotic to better orient people about health choices since primary school. Similar competencies should be disseminated to everyone through sources that are selected and validated for their capability of reporting evidence based health information about the effects of treatments.


Asunto(s)
Betacoronavirus , Difusión de la Información , Pandemias , Antivirales/uso terapéutico , Betacoronavirus/inmunología , Comunicación , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/prevención & control , Toma de Decisiones , Reposicionamiento de Medicamentos , Medicina Basada en la Evidencia , Necesidades y Demandas de Servicios de Salud , Humanos , Conducta en la Búsqueda de Información , Uso Fuera de lo Indicado , Pandemias/prevención & control , Educación del Paciente como Asunto/métodos , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto/ética , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Equipoise Terapéutico , Vacunas Virales
8.
Pathog Dis ; 78(4)2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32667665

RESUMEN

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) around the world has led to a pandemic with high morbidity and mortality. However, there are no effective drugs to prevent and treat the disease. Transcriptome-based drug repositioning, identifying new indications for old drugs, is a powerful tool for drug development. Using bronchoalveolar lavage fluid transcriptome data of COVID-19 patients, we found that the endocytosis and lysosome pathways are highly involved in the disease and that the regulation of genes involved in neutrophil degranulation was disrupted, suggesting an intense battle between SARS-CoV-2 and humans. Furthermore, we implemented a coexpression drug repositioning analysis, cogena, and identified two antiviral drugs (saquinavir and ribavirin) and several other candidate drugs (such as dinoprost, dipivefrine, dexamethasone and (-)-isoprenaline). Notably, the two antiviral drugs have also previously been identified using molecular docking methods, and ribavirin is a recommended drug in the diagnosis and treatment protocol for COVID pneumonia (trial version 5-7) published by the National Health Commission of the P.R. of China. Our study demonstrates the value of the cogena-based drug repositioning method for emerging infectious diseases, improves our understanding of SARS-CoV-2-induced disease, and provides potential drugs for the prevention and treatment of COVID-19 pneumonia.


Asunto(s)
Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Reposicionamiento de Medicamentos , Neumonía Viral/tratamiento farmacológico , Ribavirina/farmacología , Saquinavir/farmacología , Líquido del Lavado Bronquioalveolar/química , Degranulación de la Célula/inmunología , Endocitosis/inmunología , Perfilación de la Expresión Génica , Humanos , Lisosomas/inmunología , Simulación del Acoplamiento Molecular , Activación Neutrófila/inmunología , Pandemias , Transcriptoma
9.
Trials ; 21(1): 626, 2020 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-32641154

RESUMEN

OBJECTIVES: To determine if a specific immunomodulatory intervention reduces progression of COVID-19-related disease to organ failure or death, compared to standard of care (SoC). TRIAL DESIGN: Randomised, parallel 3-arm (1:1:1 ratio), open-label, Phase IV platform trial of immunomodulatory therapies in patients with late stage 1 or stage 2 COVID-19-related disease, with a diagnosis based either on a positive assay or high suspicion of COVID-19 infection by clinical and/or radiological assessment. PARTICIPANTS: Patients aged 18 and over, with a clinical picture strongly suggestive of COVID-19-related disease (with/without a positive COVID-19 test) AND a Risk count (as defined below) >3 OR ≥3 if risk count includes "Radiographic severity score >3". A risk count is calculated by the following features on admission (1 point for each): radiographic severity score >3, male gender, non-white ethnicity, diabetes, hypertension, neutrophils >8.0 x109/L, age >40 years and CRP >40 mg/L. Patients should be considered an appropriate subject for intervention with immunomodulatory therapies in the opinion of the investigator and be able to be maintained on venous thromboembolism prophylaxis during the inpatient dosing period, according to local guidelines. The complete inclusion and exclusion criteria as detailed in the additional file 1 should be fulfilled. Patients will be enrolled prior to the need for invasive mechanical ventilation, cardiac or renal support. Participants will be recruited across multiple centres including initially at Cambridge University Hospitals NHS Foundation Trust, King's College Hospital NHS Foundation Trust, Guy's and St Thomas' NHS Foundation Trust, University Hospital of Wales, Gloucestershire Royal Hospitals NHS Foundation Trust and The Royal Wolverhampton NHS Trust. INTERVENTION AND COMPARATOR: Each active comparator arm will be compared against standard of care (SoC). The immunomodulatory drugs were selected from a panel of licenced candidates by a drug evaluation committee, which considered potential efficacy, potential toxicity, scalability and novelty of each strategy. The initial active arms comprise baricitinib and ravulizumab. Baricitinib will be given 4 mg orally (once daily (OD)) on days 1-14 or until day of discharge. The dose will be reduced to 2 mg OD for patients aged > 75 years and those with an estimated Cockcroft Gault creatinine clearance of 30-60 ml/min. Ravulizumab will be administered intravenously once according to the licensed weight-based dosing regimen (see Additional file 1). Each active arm will be compared with standard of care alone. No comparisons will be made between active arms in this platform trial. MAIN OUTCOMES: The primary outcome is the incidence (from baseline up to Day 14) of any one of the events (whichever comes first): death, invasive mechanical ventilation, extra corporeal membrane oxygenation, cardiovascular organ support (inotropes or balloon pump), or renal failure (estimated Cockcroft Gault creatinine clearance <15ml/min). RANDOMISATION: Eligible patients will be randomised using a central web-based randomisation service (Sealed Envelope) in a 1:1:1 ratio, stratified by site to one of the treatment arms or SoC. BLINDING (MASKING): This is an open-label trial. Data analysis will not be blinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): There is no fixed sample size for this study. Serial interim analyses will be triggered by an Independent Data Monitoring Committee (IDMC), including analysis after 125 patients are recruited to each arm, 375 in total assuming 3 arms. Additional interim analyses are projected after 229 patients per arm, and potentially then after 469 per arm, but additional analyses may be triggered by the IDMC. TRIAL STATUS: TACTIC-R Protocol version number 2.0 date May 20, 2020, recruitment began May 7, 2020 and the end trial will be the date 18 months after the last patient's last visit. The recruitment end date cannot yet be accurately predicted. TRIAL REGISTRATION: Registered on EU Clinical Trials Register EudraCT Number: 2020-001354-22 Registered: 6 May 2020 It was registered on ClinicalTrials.gov ( NCT04390464 ) and on ISRCTN (ISRCTN11188345) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Reposicionamiento de Medicamentos , Factores Inmunológicos/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Azetidinas/efectos adversos , Azetidinas/uso terapéutico , Humanos , Unidades de Cuidados Intensivos , Pandemias , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico
10.
BMC Mol Cell Biol ; 21(1): 49, 2020 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-32611313

RESUMEN

BACKGROUND: Following the recent outbreak of the new coronavirus pandemic (Covid-19), the rapid determination of the structure of the homo-trimeric spike glycoprotein has prompted the study reported here. The aims were to identify potential "druggable" binding pockets in the protein and, if located, to virtual screen pharmaceutical agents currently in use for predicted affinity to these pockets which might be useful to restrict, reduce, or inhibit the infectivity of the virion. RESULTS: Our analyses of this structure have revealed a key potentially druggable pocket where it might be viable to bind pharmaceutical agents to inhibit its ability to infect human cells. This pocket is found at the inter-chain interface that exists between two domains prior to the virion binding to human Angiotensin Converting Enzyme 2 (ACE2) protein. One of these domains is the highly mobile receptor binding domain, which must move into position to interact with ACE2, which is an essential feature for viral entry to the host cell. Virtual screening with a library of purchasable drug molecules has identified pharmaceuticals currently in use as prescription and over the counter medications that, in silico, readily bind into this pocket. CONCLUSIONS: This study highlights possible drugs already in use as pharmaceuticals that may act as agents to interfere with the movements of the domains within this protein essential for the infectivity processes and hence might slow, or even halt, the infection of host cells by this new coronavirus. As these are existing pharmaceuticals already approved for use in humans, this knowledge could accelerate their roll-out, through repurposing, for affected individuals and help guide the efforts of other researchers in finding effective treatments for the disease.


Asunto(s)
Antivirales/farmacología , Sitios de Unión/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Reposicionamiento de Medicamentos , Neumonía Viral/tratamiento farmacológico , Glicoproteína de la Espiga del Coronavirus/metabolismo , Secuencia de Aminoácidos , Betacoronavirus/efectos de los fármacos , Humanos , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Dominios Proteicos/efectos de los fármacos , Glicoproteína de la Espiga del Coronavirus/química , Internalización del Virus/efectos de los fármacos
12.
Commun Biol ; 3(1): 374, 2020 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-32641750

RESUMEN

The recent outbreak of infections and the pandemic caused by SARS-CoV-2 represent one of the most severe threats to human health in more than a century. Emerging data from the United States and elsewhere suggest that the disease is more severe in men. Knowledge gained, and lessons learned, from studies of the biological interactions and molecular links that may explain the reasons for the greater severity of disease in men, and specifically in the age group at risk for prostate cancer, will lead to better management of COVID-19 in prostate cancer patients. Such information will be indispensable in the current and post-pandemic scenarios.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/epidemiología , Pandemias , Neumonía Viral/epidemiología , Neoplasias de la Próstata/epidemiología , Distribución por Sexo , Antineoplásicos Hormonales/uso terapéutico , Antivirales/uso terapéutico , Betacoronavirus/fisiología , Betacoronavirus/ultraestructura , Comorbilidad , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Susceptibilidad a Enfermedades , Reposicionamiento de Medicamentos , Femenino , Predicción , Hormonas Esteroides Gonadales/fisiología , Humanos , Masculino , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/fisiología , Peptidil-Dipeptidasa A/fisiología , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/inmunología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Inhibidores de Proteasas/uso terapéutico , Receptores Virales/efectos de los fármacos , Receptores Virales/fisiología , Factores de Riesgo , Serina Endopeptidasas/biosíntesis , Serina Endopeptidasas/fisiología , Estados Unidos/epidemiología , Internalización del Virus
13.
J Int Med Res ; 48(7): 300060520939746, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32722979

RESUMEN

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 infection is a serious global concern. Increased morbidity and mortality is associated with older age, male gender, cardiovascular disease, diabetes, and smoking. As COVID-19 spreads from coastal borders, both state to state and country to country, our understanding of its pathophysiology has evolved. Age and type 2 diabetes mellitus (T2DM) play especially important roles in COVID-19 progression. T2DM is an age-related disease associated with metabolic syndrome, obesity, insulin resistance (hyperinsulinemia), hyperlipidemia, hypertension, hyperglycemia, and endothelial activation and dysfunction. This review evaluates the relationships and intersection between endothelial cell activation and dysfunction in T2DM and COVID-19. COVID-19 induces multiple injuries of the terminal bronchioles and alveolar blood-gas barrier and associated ultrastructural tissue remodeling. COVID-19 may unmask multiple vulnerabilities associated with T2DM including damage to the endothelial glycocalyx and multiple end-organ macro and microvascular diseases. Unmasking existing vulnerabilities in diabetic patients with COVID-19 is important. Globally, we must come together to better understand why T2DM is associated with increased COVID-19 morbidity and mortality.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Células Endoteliales/fisiología , Síndrome Metabólico/complicaciones , Síndrome Metabólico/fisiopatología , Neumonía Viral/complicaciones , Neumonía Viral/fisiopatología , Animales , Barrera Alveolocapilar/patología , Barrera Alveolocapilar/fisiopatología , Bronquiolos/patología , Bronquiolos/fisiopatología , Comorbilidad , Infecciones por Coronavirus/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Reposicionamiento de Medicamentos , Células Endoteliales/patología , Humanos , Síndrome Metabólico/epidemiología , Modelos Biológicos , Pandemias , Neumonía Viral/epidemiología , Alveolos Pulmonares/fisiología , Alveolos Pulmonares/fisiopatología , Ratas , Cicatrización de Heridas/fisiología
15.
BMC Bioinformatics ; 21(1): 313, 2020 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-32677879

RESUMEN

BACKGROUND: Drug repurposing aims to detect the new therapeutic benefits of the existing drugs and reduce the spent time and cost of the drug development projects. The synthetic repurposing of drugs may prove to be more useful than the single repurposing in terms of reducing toxicity and enhancing efficacy. However, the researchers have not given it serious consideration. To address the issue, a novel datamining method is introduced and applied to repositioning of drugs for hypertension (HT) which is a serious medical condition and needs some improved treatment plans to help treat it. RESULTS: A novel two-step data mining method, which is based on the If-Then association rules as well as a novel discrete optimization algorithm, was introduced and applied to the synthetic repurposing of drugs for HT. The required data were also extracted from DrugBank, KEGG, and DrugR+ databases. The findings indicated that based on the different statistical criteria, the proposed method outperformed the other state-of-the-art approaches. In contrast to the previously proposed methods which had failed to discover a list on some datasets, our method could find a combination list for all of them. CONCLUSION: Since the proposed synthetic method uses medications in small dosages, it might revive some failed drug development projects and put forward a suitable plan for treating different diseases such as COVID-19 and HT. It is also worth noting that applying efficient computational methods helps to produce better results.


Asunto(s)
Antihipertensivos/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Minería de Datos , Reposicionamiento de Medicamentos , Neumonía Viral/tratamiento farmacológico , Algoritmos , Betacoronavirus , Bases de Datos Factuales , Humanos , Aprendizaje Automático , Pandemias
16.
Biomolecules ; 10(6)2020 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-32599963

RESUMEN

The pandemic associated with Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV2) and its disease named COVID-19 challenged the scientific community to discover effective therapeutic solutions in a short period. Repurposing existing drugs is one viable approach that emphasizes speed during these urgent times. Famotidine, a class A G protein-coupled receptor antagonist used for the treatment of gastroesophageal reflux was recently identified in an in silico screening. Additionally, a recent retrospective clinical report showed that the treatment with famotidine provided a good outcome in patients infected with SARS-CoV2. A clinical trial testing effectiveness of famotidine in combination with hydroxychloroquine is currently ongoing in the United States (US). In the 1990s, famotidine was described as an antiviral agent against human immunodeficiency virus (HIV). Interestingly, some HIV protease inhibitors are presently being used against SARS-CoV2. However, it is not clear if famotidine could be effective against SARS-CoV2. Thus, by using a computational analysis, we aimed to examine if the antiviral effect of famotidine could be related to the inhibition of proteases involved in the virus replication. Our results showed that famotidine could interact within the catalytic site of the three proteases associated with SARS-CoV2 replication. However, weak binding affinity of famotidine to these proteases suggests that a successful famotidine therapy could likely be achieved only in combination with other antiviral drugs. Finally, analysis of famotidine's pharmacokinetic parameters indicated that its effect against SARS-CoV2 infection could be reached only upon intravenous administration. This work will contribute to the pharmacological knowledge of famotidine as an antiviral agent against SARS-CoV2.


Asunto(s)
Antivirales/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Famotidina/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Administración Intravenosa , Antivirales/administración & dosificación , Antivirales/farmacocinética , Simulación por Computador , Reposicionamiento de Medicamentos , Famotidina/administración & dosificación , Famotidina/farmacocinética , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Pandemias , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/uso terapéutico , Replicación Viral/efectos de los fármacos
17.
Int J Mol Sci ; 21(14)2020 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-32708196

RESUMEN

(1) Background: Virtual screening studies on the therapeutically relevant proteins of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) require a detailed characterization of their druggable binding sites, and, more generally, a convenient pocket mapping represents a key step for structure-based in silico studies; (2) Methods: Along with a careful literature search on SARS-CoV-2 protein targets, the study presents a novel strategy for pocket mapping based on the combination of pocket (as performed by the well-known FPocket tool) and docking searches (as performed by PLANTS or AutoDock/Vina engines); such an approach is implemented by the Pockets 2.0 plug-in for the VEGA ZZ suite of programs; (3) Results: The literature analysis allowed the identification of 16 promising binding cavities within the SARS-CoV-2 proteins and the here proposed approach was able to recognize them showing performances clearly better than those reached by the sole pocket detection; and (4) Conclusions: Even though the presented strategy should require more extended validations, this proved successful in precisely characterizing a set of SARS-CoV-2 druggable binding pockets including both orthosteric and allosteric sites, which are clearly amenable for virtual screening campaigns and drug repurposing studies. All results generated by the study and the Pockets 2.0 plug-in are available for download.


Asunto(s)
Antivirales/química , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Proteínas Virales/química , Sitios de Unión/efectos de los fármacos , Reposicionamiento de Medicamentos , Humanos , Simulación del Acoplamiento Molecular , Pandemias , Unión Proteica/efectos de los fármacos , Conformación Proteica
18.
J Biosci ; 452020.
Artículo en Inglés | MEDLINE | ID: mdl-32713863

RESUMEN

The world is currently facing the COVID-19 pandemic, for which mild symptoms include fever and dry cough. In severe cases, it could lead to pneumonia and ultimately death in some instances. Moreover, the causative pathogen is highly contagious and there are no drugs or vaccines for it yet. The pathogen, SARS-CoV-2, is one of the human coronaviruses which was identified to infect humans first in December 2019. SARS-CoV-2 shares evolutionary relationship to other highly pathogenic viruses such as Severe Acute Respiratory Syndrome (SARS) and Middle East respiratory syndrome (MERS). We have exploited this similarity to model a target non-structural protein, NSP1, since it is implicated in the regulation of host gene expression by the virus and hijacking of host machinery. We next interrogated the capacity to repurpose around 2300 FDA-approved drugs and more than 3,00,000 small molecules of natural origin towards drug identification through virtual screening and molecular dynamics. Interestingly, we observed simple molecules like lactose, previously known anti-virals and few secondary metabolites of plants as promising hits. These herbal plants are already practiced in Ayurveda over centuries to treat respiratory problems and inflammation. Disclaimer: we would not like to recommend uptake of these small molecules for suspect COVID patients until it is approved by competent national or international authorities.


Asunto(s)
Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Descubrimiento de Drogas , Reposicionamiento de Medicamentos , Neumonía Viral/tratamiento farmacológico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Pandemias , Extractos Vegetales/uso terapéutico , Conformación Proteica
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