Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.418
Filtrar
1.
Top Curr Chem (Cham) ; 379(6): 40, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34623536

RESUMO

The highly infectious disease COVID-19 is induced by SARS-coronavirus 2 (SARS-CoV-2), which has spread rapidly around the globe and was announced as a pandemic by the World Health Organization (WHO) in March 2020. SARS-CoV-2 binds to the host cell's angiotensin converting enzyme 2 (ACE2) receptor through the viral surface spike glycoprotein (S-protein). ACE2 is expressed in the oral mucosa and can therefore constitute an essential route for entry of SARS-CoV-2 into hosts through the tongue and lung epithelial cells. At present, no effective treatments for SARS-CoV-2 are yet in place. Blocking entry of the virus by inhibiting ACE2 is more advantageous than inhibiting the subsequent stages of the SARS-CoV-2 life cycle. Based on current published evidence, we have summarized the different in silico based studies and repurposing of anti-viral drugs to target ACE2, SARS-CoV-2 S-Protein: ACE2 and SARS-CoV-2 S-RBD: ACE2. This review will be useful to researchers looking to effectively recognize and deal with SARS-CoV-2, and in the development of repurposed ACE2 inhibitors against COVID-19.


Assuntos
Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Reposicionamento de Medicamentos , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Internalização do Vírus/efeitos dos fármacos , Animais , Humanos
2.
Sci Rep ; 11(1): 19426, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34593915

RESUMO

The COVID-19 pandemic poses a huge problem of public health that requires the implementation of all available means to contrast it, and drugs are one of them. In this context, we observed an unmet need of depicting the continuously evolving scenario of the ongoing drug clinical trials through an easy-to-use, freely accessible online tool. Starting from this consideration, we developed COVIDrugNet ( http://compmedchem.unibo.it/covidrugnet ), a web application that allows users to capture a holistic view and keep up to date on how the clinical drug research is responding to the SARS-CoV-2 infection. Here, we describe the web app and show through some examples how one can explore the whole landscape of medicines in clinical trial for the treatment of COVID-19 and try to probe the consistency of the current approaches with the available biological and pharmacological evidence. We conclude that careful analyses of the COVID-19 drug-target system based on COVIDrugNet can help to understand the biological implications of the proposed drug options, and eventually improve the search for more effective therapies.


Assuntos
COVID-19/tratamento farmacológico , Biologia Computacional/métodos , Ensaios Clínicos como Assunto , Biologia Computacional/instrumentação , Bases de Dados de Produtos Farmacêuticos , Reposicionamento de Medicamentos , Humanos , Internet , Proteínas Virais/metabolismo
3.
Sci Rep ; 11(1): 19481, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34593970

RESUMO

The pandemic infectious disease (Covid-19) caused by the coronavirus (SARS-CoV2) is spreading rapidly around the world. Covid-19 does an irreparable harm to the health and life of people. It also has a negative financial impact on the economies of most countries of the world. In this regard, the issue of creating drugs aimed at combating this disease is especially acute. In this work, molecular docking was used to study the docking of 23 compounds with QRF3a SARS-CoV2. The performed in silico modeling made it possible to identify leading compounds capable of exerting a potential inhibitory and virucidal effect. The leading compounds include chlorin (a drug used in PDT), iron(III)protoporphyrin (endogenous porphyrin), and tetraanthraquinone porphyrazine (an exogenous substance). Having taken into consideration the localization of ligands in the QRF3a SARS-CoV2, we have made an assumption about their influence on the pathogenesis of Covid-19. The interaction of chlorin, iron(III)protoporphyrin and protoporphyrin with the viral protein ORF3a were studied by fluorescence and UV-Vis spectroscopy. The obtained experimental results confirm the data of molecular docking. The results showed that a viral protein binds to endogenous porphyrins and chlorins, moreover, chlorin is a competitive ligand for endogenous porphyrins. Chlorin should be considered as a promising drug for repurposing.


Assuntos
Antivirais/química , Antivirais/metabolismo , Compostos Heterocíclicos/química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/metabolismo , Proteínas Viroporinas/química , Proteínas Viroporinas/metabolismo , Sítios de Ligação , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , Compostos Heterocíclicos/metabolismo , Ligantes , Simulação de Acoplamento Molecular , Porfirinas/química , Porfirinas/metabolismo , Protoporfirinas/química , Protoporfirinas/metabolismo , SARS-CoV-2/efeitos dos fármacos , Proteínas Viroporinas/antagonistas & inibidores
4.
J Mol Model ; 27(11): 312, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34601658

RESUMO

A novel coronavirus known as severe acute respiratory syndrome is rapidly spreading worldwide. The international health authorities are putting all their efforts on quick diagnosis and placing the patients in quarantine. Although different vaccines have come for quick use as prophylactics, drug repurposing seems to be of paramount importance because of inefficient therapeutic options and clinical trial limitations. Here, we used structure-based drug designing approach to find and check the efficacy of the possible drug that can inhibit coronavirus main protease which is involved in polypeptide processing to functional protein. We performed virtual screening, molecular docking and molecular dynamics simulations of the FDA-approved drugs against the main protease of SARS-CoV-2. Using well-defined computational methods, we identified amprenavir, cefoperazone, riboflavin, diosmin, nadide and troxerutin approved for human therapeutic uses, as COVID-19 main protease inhibitors. These drugs bind to the SARS-CoV-2 main protease conserved residues of substrate-binding pocket and formed a remarkable number of non-covalent interactions. We have found diosmin as an inhibitor which binds covalently to the COVID-19 main protease. This study provides enough evidences for therapeutic use of these drugs in controlling COVID-19 after experimental validation and clinical demonstration.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , Inibidores de Proteases/farmacologia , SARS-CoV-2/efeitos dos fármacos , COVID-19/virologia , Aprovação de Drogas , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estados Unidos , United States Food and Drug Administration
6.
Comput Biol Med ; 137: 104826, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34537409

RESUMO

Corona Virus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become a global pandemic. Additionally, the SARS-CoV-2 infection in the patients of Gastric Cancer (GC; the third leading cause of death in the world) pose a great challenge for the health management of the patients. Since there have been uncertainties to develop a new drug against COVID-19, there is an urgent need for repurposing drugs that can target key proteins of both SARS-CoV-2 and GC. The SARS-CoV-2-RdRp protein contains the NiRAN domain, which is known to have kinase-like folds. A docking study of the FDA approved drugs against GC was performed using AutoDock 4.2 and Glide Schrodinger suite 2019 against SARS-CoV-2-RdRp protein. MMGBSA and MD simulation studies were performed to investigate the binding and stability of the inhibitors with the target protein. In this study, we have found 12 kinase inhibitors with high binding energies namely Baricitinib, Brepocitinib, Decernotinib, Fasudil, Filgotinib, GSK2606414, Peficitinib, Ruxolitinib, Tofacitinib, Upadacitinib, Pamapimod and Ibrutinib. These FDA approved drugs against GC can play a key role in the treatment of COVID-19 patients along with GC as comorbidity. We also hypothesize that JAK, ITK, Rho-associated kinases, FGFR2, FYN, PERK, TYK2, p38-MAPK and SYK kinases can be considered as key therapeutic targets in COVID-19 treatment. Taken altogether, we have proposed the SARS-CoV-2-RdRp as a potential therapeutic target through in-silico studies. However, further in-vitro and in-vivo studies are required for the validation of the proposed targets and drugs for the treatment of COVID-19 patients already suffering from GC.


Assuntos
COVID-19 , Preparações Farmacêuticas , Neoplasias Gástricas , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , Fármacos Gastrointestinais , Humanos , SARS-CoV-2 , Neoplasias Gástricas/tratamento farmacológico
7.
Front Cell Infect Microbiol ; 11: 657257, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34476220

RESUMO

T. cruzi, the causal agent of Chagas disease, is a parasite able to infect different types of host cells and to persist chronically in the tissues of human and animal hosts. These qualities and the lack of an effective treatment for the chronic stage of the disease have contributed to the durability and the spread of the disease around the world. There is an urgent necessity to find new therapies for Chagas disease. Drug repurposing is a promising and cost-saving strategy for finding new drugs for different illnesses. In this work we describe the effect of carvedilol on T. cruzi. This compound, selected by virtual screening, increased the accumulation of immature autophagosomes characterized by lower acidity and hydrolytic properties. As a consequence of this action, the survival of trypomastigotes and the replication of epimastigotes and amastigotes were impaired, resulting in a significant reduction of infection and parasite load. Furthermore, carvedilol reduced the whole-body parasite burden peak in infected mice. In summary, in this work we present a repurposed drug with a significant in vitro and in vivo activity against T. cruzi. These data in addition to other pharmacological properties make carvedilol an attractive lead for Chagas disease treatment.


Assuntos
Parasitos , Trypanosoma cruzi , Animais , Autofagia , Carvedilol/farmacologia , Reposicionamento de Medicamentos , Camundongos
8.
J Integr Med ; 19(5): 375-388, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34479848

RESUMO

Artemisia annua and its phytocompounds have a rich history in the research and treatment of malaria, rheumatoid arthritis, systemic lupus erythematosus, and other diseases. Currently, the World Health Organization recommends artemisinin-based combination therapy as the first-line treatment for multi-drug-resistant malaria. Due to the various research articles on the use of antimalarial drugs to treat coronaviruses, a question is raised: would A. annua and its compounds provide anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) properties? PubMed/MEDLINE, Scopus, and Google Scholar were searched for peer-reviewed articles that investigated the antiviral effects and mechanisms of A. annua and its phytochemicals against SARS-CoVs. Particularly, articles that evidenced the herb's role in inhibiting the coronavirus-host proteins were favored. Nineteen studies were retrieved. From these, fourteen in silico molecular docking studies demonstrated potential inhibitory properties of artemisinins against coronavirus-host proteins including 3CLPRO, S protein, N protein, E protein, cathepsin-L, helicase protein, nonstructural protein 3 (nsp3), nsp10, nsp14, nsp15, and glucose-regulated protein 78 receptor. Collectively, A. annua constituents may impede the SARS-CoV-2 attachment, membrane fusion, internalization into the host cells, and hinder the viral replication and transcription process. This is the first comprehensive overview of the application of compounds from A. annua against SARS-CoV-2/coronavirus disease 2019 (COVID-19) describing all target proteins. A. annua's biological properties, the signaling pathways implicated in the COVID-19, and the advantages and disadvantages for repurposing A. annua compounds are discussed. The combination of A. annua's biological properties, action on different signaling pathways and target proteins, and a multi-drug combined-therapy approach may synergistically inhibit SARS-CoV-2 and assist in the COVID-19 treatment. Also, A. annua may modulate the host immune response to better fight the infection.


Assuntos
Artemisia annua , COVID-19 , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , Humanos , Simulação de Acoplamento Molecular , SARS-CoV-2
9.
Sci Rep ; 11(1): 18985, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34556735

RESUMO

The COVID-19 pandemic is raging. It revealed the importance of rapid scientific advancement towards understanding and treating new diseases. To address this challenge, we adapt an explainable artificial intelligence algorithm for data fusion and utilize it on new omics data on viral-host interactions, human protein interactions, and drugs to better understand SARS-CoV-2 infection mechanisms and predict new drug-target interactions for COVID-19. We discover that in the human interactome, the human proteins targeted by SARS-CoV-2 proteins and the genes that are differentially expressed after the infection have common neighbors central in the interactome that may be key to the disease mechanisms. We uncover 185 new drug-target interactions targeting 49 of these key genes and suggest re-purposing of 149 FDA-approved drugs, including drugs targeting VEGF and nitric oxide signaling, whose pathways coincide with the observed COVID-19 symptoms. Our integrative methodology is universal and can enable insight into this and other serious diseases.


Assuntos
COVID-19/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , SARS-CoV-2/genética , Antivirais/uso terapêutico , Inteligência Artificial , COVID-19/genética , COVID-19/metabolismo , Reposicionamento de Medicamentos/métodos , Redes Reguladoras de Genes/genética , Humanos , Modelos Teóricos , Pandemias , Preparações Farmacêuticas , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Transdução de Sinais/genética
10.
Sci Rep ; 11(1): 17810, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497279

RESUMO

Transporters in the human liver play a major role in the clearance of endo- and xenobiotics. Apical (canalicular) transporters extrude compounds to the bile, while basolateral hepatocyte transporters promote the uptake of, or expel, various compounds from/into the venous blood stream. In the present work we have examined the in vitro interactions of some key repurposed drugs advocated to treat COVID-19 (lopinavir, ritonavir, ivermectin, remdesivir and favipiravir), with the key drug transporters of hepatocytes. These transporters included ABCB11/BSEP, ABCC2/MRP2, and SLC47A1/MATE1 in the canalicular membrane, as well as ABCC3/MRP3, ABCC4/MRP4, SLC22A1/OCT1, SLCO1B1/OATP1B1, SLCO1B3/OATP1B3, and SLC10A1/NTCP, residing in the basolateral membrane. Lopinavir and ritonavir in low micromolar concentrations inhibited BSEP and MATE1 exporters, as well as OATP1B1/1B3 uptake transporters. Ritonavir had a similar inhibitory pattern, also inhibiting OCT1. Remdesivir strongly inhibited MRP4, OATP1B1/1B3, MATE1 and OCT1. Favipiravir had no significant effect on any of these transporters. Since both general drug metabolism and drug-induced liver toxicity are strongly dependent on the functioning of these transporters, the various interactions reported here may have important clinical relevance in the drug treatment of this viral disease and the existing co-morbidities.


Assuntos
Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antivirais/farmacologia , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Fígado/efeitos dos fármacos , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/química , Alanina/metabolismo , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/química , Antivirais/metabolismo , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Comorbidade , Reposicionamento de Medicamentos , Humanos , Fígado/metabolismo , Fígado/patologia , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Lopinavir/química , Lopinavir/metabolismo , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Ritonavir/química , Ritonavir/metabolismo , Ritonavir/farmacologia , Ritonavir/uso terapêutico , SARS-CoV-2/isolamento & purificação , Especificidade por Substrato
11.
Trop Biomed ; 38(3): 343-352, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34508342

RESUMO

Outbreak of SARS-CoV-2 has been declared a pandemic, which is a serious threat to human health. The disease was named coronavirus disease 2019 (COVID-19). Until now, several vaccines and a few drugs have been approved for the prevention and treatment for COVID-19. Recently, the effect of some macrolides including clarithromycin (CAM) on COVID-19 has attracted attention. CAM is known to have diverse effects including immunomodulatory and immunosuppressive effects, autophagy inhibition, steroid sparing effect, reversibility of drug resistance, antineoplastic effect, antiviral effect as well as bacteriostatic/bactericidal effect. Many patients with COVID-19 died due to an overwhelming response of their own immune system characterized by the uncontrolled release of circulating inflammatory cytokines (cytokine release syndrome [CRS]). This CRS plays a major role in progressing pneumonia to acute respiratory distress syndrome (ARDS) in COVID-19 patients. It is noteworthy that CAM can suppress inflammatory cytokines responsible for CRS and also has anti-SARS-CoV-2 effect. Considering the rapidly progressive global disease burden of COVID 19, the application of CAM for treating COVID-19 needs to be urgently evaluated. Recently, an open-labeled non-randomized trial using CAM for treating COVID-19 (ACHIEVE) was initiated in Greece in May, 2020. Its results, though preprint, indicated that CAM treatment of patients with moderate COVID-19 was associated with early clinical improvement and containment of viral load. Thus, treatment with CAM as a single agent or combined with other anti-SARS CoV-2 drugs should be tried for treating COVID-19. In this article, we discussed the significance and usefulness of CAM in treating COVID-19.


Assuntos
COVID-19/tratamento farmacológico , Claritromicina/uso terapêutico , Reposicionamento de Medicamentos , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/metabolismo , Azitromicina/uso terapêutico , Claritromicina/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Fatores Imunológicos/farmacologia , SARS-CoV-2/efeitos dos fármacos
12.
PLoS Pathog ; 17(9): e1009840, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34499689

RESUMO

COVID-19 vaccines based on the Spike protein of SARS-CoV-2 have been developed that appear to be largely successful in stopping infection. However, therapeutics that can help manage the disease are still required until immunity has been achieved globally. The identification of repurposed drugs that stop SARS-CoV-2 replication could have enormous utility in stemming the disease. Here, using a nano-luciferase tagged version of the virus (SARS-CoV-2-ΔOrf7a-NLuc) to quantitate viral load, we evaluated a range of human cell types for their ability to be infected and support replication of the virus, and performed a screen of 1971 FDA-approved drugs. Hepatocytes, kidney glomerulus, and proximal tubule cells were particularly effective in supporting SARS-CoV-2 replication, which is in-line with reported proteinuria and liver damage in patients with COVID-19. Using the nano-luciferase as a measure of virus replication we identified 35 drugs that reduced replication in Vero cells and human hepatocytes when treated prior to SARS-CoV-2 infection and found amodiaquine, atovaquone, bedaquiline, ebastine, LY2835219, manidipine, panobinostat, and vitamin D3 to be effective in slowing SARS-CoV-2 replication in human cells when used to treat infected cells. In conclusion, our study has identified strong candidates for drug repurposing, which could prove powerful additions to the treatment of COVID.


Assuntos
COVID-19/tratamento farmacológico , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Animais , Biomarcadores , Linhagem Celular , Chlorocebus aethiops , Hepatócitos/virologia , Humanos , Luciferases/farmacologia , Nanoestruturas , SARS-CoV-2/genética , Células Vero , Replicação Viral/efeitos dos fármacos
13.
Mol Med ; 27(1): 105, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503440

RESUMO

BACKGROUND: Vaccination programs have been launched worldwide to halt the spread of COVID-19. However, the identification of existing, safe compounds with combined treatment and prophylactic properties would be beneficial to individuals who are waiting to be vaccinated, particularly in less economically developed countries, where vaccine availability may be initially limited. METHODS: We used a data-driven approach, combining results from the screening of a large transcriptomic database (L1000) and molecular docking analyses, with in vitro tests using a lung organoid model of SARS-CoV-2 entry, to identify drugs with putative multimodal properties against COVID-19. RESULTS: Out of thousands of FDA-approved drugs considered, we observed that atorvastatin was the most promising candidate, as its effects negatively correlated with the transcriptional changes associated with infection. Atorvastatin was further predicted to bind to SARS-CoV-2's main protease and RNA-dependent RNA polymerase, and was shown to inhibit viral entry in our lung organoid model. CONCLUSIONS: Small clinical studies reported that general statin use, and specifically, atorvastatin use, are associated with protective effects against COVID-19. Our study corroborrates these findings and supports the investigation of atorvastatin in larger clinical studies. Ultimately, our framework demonstrates one promising way to fast-track the identification of compounds for COVID-19, which could similarly be applied when tackling future pandemics.


Assuntos
Antivirais/farmacologia , Atorvastatina/farmacologia , COVID-19/tratamento farmacológico , Pulmão/efeitos dos fármacos , Organoides/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Atorvastatina/química , COVID-19/prevenção & controle , Linhagem Celular , Proteases 3C de Coronavírus/química , RNA-Polimerase RNA-Dependente de Coronavírus/química , Doxiciclina/farmacologia , Aprovação de Drogas , Reposicionamento de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/virologia , Modelos Biológicos , Simulação de Acoplamento Molecular , Organoides/virologia , Cloridrato de Raloxifeno/química , Cloridrato de Raloxifeno/farmacologia , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/genética , Trifluoperazina/química , Trifluoperazina/farmacologia , Estados Unidos , United States Food and Drug Administration , Vesiculovirus/genética , Internalização do Vírus/efeitos dos fármacos
14.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502335

RESUMO

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been identified as the pathogen responsible for the outbreak of a severe, rapidly developing pneumonia (Coronavirus disease 2019, COVID-19). The virus enzyme, called 3CLpro or main protease (Mpro), is essential for viral replication, making it a most promising target for antiviral drug development. Recently, we adopted the drug repurposing as appropriate strategy to give fast response to global COVID-19 epidemic, by demonstrating that the zonulin octapeptide inhibitor AT1001 (Larazotide acetate) binds Mpro catalytic domain. Thus, in the present study we tried to investigate the antiviral activity of AT1001, along with five derivatives, by cell-based assays. Our results provide with the identification of AT1001 peptide molecular framework for lead optimization step to develop new generations of antiviral agents of SARS-CoV-2 with an improved biological activity, expanding the chance for success in clinical trials.


Assuntos
Antivirais/farmacologia , Simulação de Acoplamento Molecular , Oligopeptídeos/química , Peptídeos/metabolismo , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Antivirais/metabolismo , Antivirais/uso terapêutico , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/virologia , Domínio Catalítico , Linhagem Celular , Citomegalovirus/efeitos dos fármacos , Reposicionamento de Medicamentos , Herpesvirus Humano 3/efeitos dos fármacos , Humanos , Simulação de Dinâmica Molecular , Peptídeos/síntese química , Peptídeos/farmacologia , Peptídeos/uso terapêutico , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/metabolismo
15.
Molecules ; 26(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34577097

RESUMO

Drug repositioning is a successful approach in medicinal research. It significantly simplifies the long-term process of clinical drug evaluation, since the drug being tested has already been approved for another condition. One example of drug repositioning involves cardiac glycosides (CGs), which have, for a long time, been used in heart medicine. Moreover, it has been known for decades that CGs also have great potential in cancer treatment and, thus, many clinical trials now evaluate their anticancer potential. Interestingly, heart failure and cancer are not the only conditions for which CGs could be effectively used. In recent years, the antiviral potential of CGs has been extensively studied, and with the ongoing SARS-CoV-2 pandemic, this interest in CGs has increased even more. Therefore, here, we present CGs as potent and promising antiviral compounds, which can interfere with almost any steps of the viral life cycle, except for the viral attachment to a host cell. In this review article, we summarize the reported data on this hot topic and discuss the mechanisms of antiviral action of CGs, with reference to the particular viral life cycle phase they interfere with.


Assuntos
Antivirais/uso terapêutico , Glicosídeos Cardíacos/uso terapêutico , Antivirais/farmacologia , COVID-19 , Glicosídeos Cardíacos/metabolismo , Digitoxina , Digoxina , Reposicionamento de Medicamentos/métodos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/virologia , Humanos , Neoplasias/tratamento farmacológico , Ouabaína , Pandemias , SARS-CoV-2 , ATPase Trocadora de Sódio-Potássio , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
16.
BMC Med Genomics ; 14(1): 226, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535131

RESUMO

BACKGROUND: Higher mortality of COVID-19 patients with lung disease is a formidable challenge for the health care system. Genetic association between COVID-19 and various lung disorders must be understood to comprehend the molecular basis of comorbidity and accelerate drug development. METHODS: Lungs tissue-specific neighborhood network of human targets of SARS-CoV-2 was constructed. This network was integrated with lung diseases to build a disease-gene and disease-disease association network. Network-based toolset was used to identify the overlapping disease modules and drug targets. The functional protein modules were identified using community detection algorithms and biological processes, and pathway enrichment analysis. RESULTS: In total, 141 lung diseases were linked to a neighborhood network of SARS-CoV-2 targets, and 59 lung diseases were found to be topologically overlapped with the COVID-19 module. Topological overlap with various lung disorders allows repurposing of drugs used for these disorders to hit the closely associated COVID-19 module. Further analysis showed that functional protein-protein interaction modules in the lungs, substantially hijacked by SARS-CoV-2, are connected to several lung disorders. FDA-approved targets in the hijacked protein modules were identified and that can be hit by exiting drugs to rescue these modules from virus possession. CONCLUSION: Lung diseases are clustered with COVID-19 in the same network vicinity, indicating the potential threat for patients with respiratory diseases after SARS-CoV-2 infection. Pathobiological similarities between lung diseases and COVID-19 and clinical evidence suggest that shared molecular features are the probable reason for comorbidity. Network-based drug repurposing approaches can be applied to improve the clinical conditions of COVID-19 patients.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Reposicionamento de Medicamentos , Pneumopatias/epidemiologia , Pandemias , SARS-CoV-2 , Algoritmos , Antivirais/uso terapêutico , COVID-19/genética , Comorbidade , Descoberta de Drogas , Reposicionamento de Medicamentos/métodos , Redes Reguladoras de Genes/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Pneumopatias/tratamento farmacológico , Pneumopatias/genética , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , Biologia de Sistemas
17.
Molecules ; 26(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34500568

RESUMO

In silico target fishing, whose aim is to identify possible protein targets for a query molecule, is an emerging approach used in drug discovery due its wide variety of applications. This strategy allows the clarification of mechanism of action and biological activities of compounds whose target is still unknown. Moreover, target fishing can be employed for the identification of off targets of drug candidates, thus recognizing and preventing their possible adverse effects. For these reasons, target fishing has increasingly become a key approach for polypharmacology, drug repurposing, and the identification of new drug targets. While experimental target fishing can be lengthy and difficult to implement, due to the plethora of interactions that may occur for a single small-molecule with different protein targets, an in silico approach can be quicker, less expensive, more efficient for specific protein structures, and thus easier to employ. Moreover, the possibility to use it in combination with docking and virtual screening studies, as well as the increasing number of web-based tools that have been recently developed, make target fishing a more appealing method for drug discovery. It is especially worth underlining the increasing implementation of machine learning in this field, both as a main target fishing approach and as a further development of already applied strategies. This review reports on the main in silico target fishing strategies, belonging to both ligand-based and receptor-based approaches, developed and applied in the last years, with a particular attention to the different web tools freely accessible by the scientific community for performing target fishing studies.


Assuntos
Preparações Farmacêuticas/administração & dosagem , Animais , Simulação por Computador , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Polifarmacologia , Proteínas/metabolismo
18.
Sci Rep ; 11(1): 17915, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504128

RESUMO

Coronavirus disease 2019 (Covid-19), caused by novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), has come to the fore in Wuhan, China in December 2019 and has been spreading expeditiously all over the world due to its high transmissibility and pathogenicity. From the outbreak of COVID-19, many efforts are being made to find a way to fight this pandemic. More than 300 clinical trials are ongoing to investigate the potential therapeutic option for preventing/treating COVID-19. Considering the critical role of SARS-CoV-2 main protease (Mpro) in pathogenesis being primarily involved in polyprotein processing and virus maturation, it makes SARS-CoV-2 main protease (Mpro) as an attractive and promising antiviral target. Thus, in our study, we focused on SARS-CoV-2 main protease (Mpro), used machine learning algorithms and virtually screened small derivatives of anthraquinolone and quinolizine from PubChem that may act as potential inhibitor. Prioritisation of cavity atoms obtained through pharmacophore mapping and other physicochemical descriptors of the derivatives helped mapped important chemical features for ligand binding interaction and also for synergistic studies with molecular docking. Subsequently, these studies outcome were supported through simulation trajectories that further proved anthraquinolone and quinolizine derivatives as potential small molecules to be tested experimentally in treating COVID-19 patients.


Assuntos
Antraquinonas/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Quinolizinas/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Biologia Computacional , Proteases 3C de Coronavírus/antagonistas & inibidores , Reposicionamento de Medicamentos , Humanos , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas não Estruturais Virais/efeitos dos fármacos
19.
J Biomed Inform ; 122: 103902, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34481057

RESUMO

The effectiveness of machine learning models to provide accurate and consistent results in drug discovery and clinical decision support is strongly dependent on the quality of the data used. However, substantive amounts of open data that drive drug discovery suffer from a number of issues including inconsistent representation, inaccurate reporting, and incomplete context. For example, databases of FDA-approved drug indications used in computational drug repositioning studies do not distinguish between treatments that simply offer symptomatic relief from those that target the underlying pathology. Moreover, drug indication sources often lack proper provenance and have little overlap. Consequently, new predictions can be of poor quality as they offer little in the way of new insights. Hence, work remains to be done to establish higher quality databases of drug indications that are suitable for use in drug discovery and repositioning studies. Here, we report on the combination of weak supervision (i.e., programmatic labeling and crowdsourcing) and deep learning methods for relation extraction from DailyMed text to create a higher quality drug-disease relation dataset. The generated drug-disease relation data shows a high overlap with DrugCentral, a manually curated dataset. Using this dataset, we constructed a machine learning model to classify relations between drugs and diseases from text into four categories; treatment, symptomatic relief, contradiction, and effect, exhibiting an improvement of 15.5% with Bi-LSTM (F1 score of 71.8%) over the best performing discrete method. Access to high quality data is crucial to building accurate and reliable drug repurposing prediction models. Our work suggests how the combination of crowds, experts, and machine learning methods can go hand-in-hand to improve datasets and predictive models.


Assuntos
Crowdsourcing , Aprendizado de Máquina , Reposicionamento de Medicamentos
20.
PLoS One ; 16(9): e0257784, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34582497

RESUMO

Drug repurposing has the potential to bring existing de-risked drugs for effective intervention in an ongoing pandemic-COVID-19 that has infected over 131 million, with 2.8 million people succumbing to the illness globally (as of April 04, 2021). We have used a novel `gene signature'-based drug repositioning strategy by applying widely accepted gene ranking algorithms to prioritize the FDA approved or under trial drugs. We mined publically available RNA sequencing (RNA-Seq) data using CLC Genomics Workbench 20 (QIAGEN) and identified 283 differentially expressed genes (FDR<0.05, log2FC>1) after a meta-analysis of three independent studies which were based on severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection in primary human airway epithelial cells. Ingenuity Pathway Analysis (IPA) revealed that SARS-CoV-2 activated key canonical pathways and gene networks that intricately regulate general anti-viral as well as specific inflammatory pathways. Drug database, extracted from the Metacore and IPA, identified 15 drug targets (with information on COVID-19 pathogenesis) with 46 existing drugs as potential-novel candidates for repurposing for COVID-19 treatment. We found 35 novel drugs that inhibit targets (ALPL, CXCL8, and IL6) already in clinical trials for COVID-19. Also, we found 6 existing drugs against 4 potential anti-COVID-19 targets (CCL20, CSF3, CXCL1, CXCL10) that might have novel anti-COVID-19 indications. Finally, these drug targets were computationally prioritized based on gene ranking algorithms, which revealed CXCL10 as the common and strongest candidate with 2 existing drugs. Furthermore, the list of 283 SARS-CoV-2-associated proteins could be valuable not only as anti-COVID-19 targets but also useful for COVID-19 biomarker development.


Assuntos
COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , SARS-CoV-2/genética , Antivirais/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Células Epiteliais/efeitos dos fármacos , Epitélio/efeitos dos fármacos , Humanos , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/virologia , Sistema Respiratório/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...