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1.
Pestic Biochem Physiol ; 171: 104740, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33357562

RESUMEN

A series of new 1-tert-butyl-5-amino-4-pyrazole bioxadiazole sulfide derivatives containing a 1,3,4-oxadiazole moiety were designed and synthesized. The bioactivity results showed that some title compounds exhibited excellent protective activity against TMV and certain insecticidal activity. Among the tested compounds, the EC50 values of 5d, 5j, 5k and 5l were 165.8, 163.2, 159.7 and 193.1 mg/L, respectively, which are better than the EC50 value of ningnanmycin (271.3 mg/L). The chlorophyll contents and the defense enzyme activities of the tobacco leaves after treatment with 5j were significantly increased, which indicated that this series of title compounds may induce the systemic acquired resistance of host to defend against diseases. Further in vivo protective activity research on 5j using TMV with a GFP gene tag found that it can effectively inhibit the spread of TMV in inoculated tobacco. A morphological study with TEM revealed that title compound 5h can cause a distinct break of the rod-shaped TMV. Moreover, the insecticidal activity revealed that the fatality rates of 5a, 5b and 5m against aphidoidea were 85%, 83% and 87%, respectively, which indicated that the title compounds can effectively block the common carrier of plant viruses, thereby effectively reducing the TMV infection risk of tobacco. This series of synergistic effects provide key information for the research and development of antiviral agents.


Asunto(s)
Antivirales , Virus del Mosaico del Tabaco , Antivirales/farmacología , Diseño de Fármacos , Oxadiazoles , Pirazoles/farmacología , Relación Estructura-Actividad , Sulfuros
3.
J Virol Methods ; 287: 113995, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33068703

RESUMEN

Towards the end of 2019, a novel coronavirus (CoV) named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), genetically similar to severe acute respiratory syndrome coronavirus (SARS-CoV), emerged in Wuhan, Hubei province of China, and has been responsible for coronavirus disease 2019 (COVID-19) in humans. Since its first report, SARS-CoV-2 has resulted in a global pandemic, with over 10 million human infections and over 560,000 deaths reported worldwide at the end of June 2020. Currently, there are no United States (US) Food and Drug Administration (FDA)-approved vaccines and/or antivirals licensed against SARS-CoV-2. The high economical and health impacts of SARS-CoV-2 has placed global pressure on the scientific community to identify effective prophylactic and therapeutic treatments for SARS-CoV-2 infection and associated COVID-19 disease. While some compounds have been already reported to reduce SARS-CoV-2 infection and a handful of monoclonal antibodies (mAbs) have been described that neutralize SARS-CoV-2, there is an urgent need for the development and standardization of assays which can be used in high through-put screening (HTS) settings to identify new antivirals and/or neutralizing mAbs against SARS-CoV-2. Here, we described a rapid, accurate, and highly reproducible plaque reduction microneutralization (PRMNT) assay that can be quickly adapted for the identification and characterization of both neutralizing mAbs and antivirals against SARS-CoV-2. Importantly, our MNA is compatible with HTS settings to interrogate large and/or complex libraries of mAbs and/or antivirals to identify those with neutralizing and/or antiviral activity, respectively, against SARS-CoV-2.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Antivirales/farmacología , Pruebas de Neutralización/métodos , /inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Chlorocebus aethiops , Ensayos Analíticos de Alto Rendimiento , Humanos , Células Vero , Ensayo de Placa Viral , Replicación Viral/efectos de los fármacos
4.
Life Sci Alliance ; 4(1)2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33234678

RESUMEN

Viruses rely on their host for reproduction. Here, we made use of genomic and structural information to create a biomass function capturing the amino and nucleic acid requirements of SARS-CoV-2. Incorporating this biomass function into a stoichiometric metabolic model of the human lung cell and applying metabolic flux balance analysis, we identified host-based metabolic perturbations inhibiting SARS-CoV-2 reproduction. Our results highlight reactions in the central metabolism, as well as amino acid and nucleotide biosynthesis pathways. By incorporating host cellular maintenance into the model based on available protein expression data from human lung cells, we find that only few of these metabolic perturbations are able to selectively inhibit virus reproduction. Some of the catalysing enzymes of such reactions have demonstrated interactions with existing drugs, which can be used for experimental testing of the presented predictions using gene knockouts and RNA interference techniques. In summary, the developed computational approach offers a platform for rapid, experimentally testable generation of drug predictions against existing and emerging viruses based on their biomass requirements.


Asunto(s)
Interacciones Huésped-Patógeno , Pulmón , Replicación Viral , Antivirales/farmacología , Biomasa , /virología , Células Cultivadas , Medios de Cultivo/química , Medios de Cultivo/metabolismo , Glucólisis/fisiología , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/fisiología , Humanos , Pulmón/citología , Pulmón/metabolismo , Análisis de Flujos Metabólicos , Modelos Biológicos , /metabolismo , Biología de Sistemas , Replicación Viral/efectos de los fármacos , Replicación Viral/fisiología
6.
J Hepatol ; 74(1): 168-184, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33038433

RESUMEN

Coronavirus disease 2019 (COVID-19) started as an epidemic in Wuhan in 2019, and has since become a pandemic. Groups from China identified and sequenced the virus responsible for COVID-19, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and determined that it was a novel coronavirus sharing high sequence identity with bat- and pangolin-derived SARS-like coronaviruses, suggesting a zoonotic origin. SARS-CoV-2 is a member of the Coronaviridae family of enveloped, positive-sense, single-stranded RNA viruses that infect a broad range of vertebrates. The rapid release of the sequence of the virus has enabled the development of diagnostic tools. Additionally, serological tests can now identify individuals who have been infected. SARS-CoV-2 infection is associated with a fatality rate of around 1-3%, which is commonly linked to the development of acute respiratory distress syndrome (ARDS), likely resulting from uncontrolled immune activation, the so called "cytokine storm". Risk factors for mortality include advanced age, obesity, diabetes, and hypertension. Drug repurposing has been used to rapidly identify potential treatments for COVID-19, which could move quickly to phase III. Better knowledge of the virus and its enzymes will aid the development of more potent and specific direct-acting antivirals. In the long term, a vaccine to prevent infection is crucial; however, even if successful, it might not be available before 2021-22. To date, except for intravenous remdesivir and dexamethasone, which have modest effects in moderate to severe COVID-19, no strong clinical evidence supports the efficacy of any other drugs against SARS-CoV-2. The aim of this review is to provide insights on the discovery of SARS-CoV-2, its virology, diagnostic tools, and the ongoing drug discovery effort.


Asunto(s)
Antivirales/farmacología , Desarrollo de Medicamentos , Descubrimiento de Drogas , /efectos de los fármacos , /diagnóstico , /fisiopatología , Reposicionamiento de Medicamentos , Genoma Viral , Humanos , Inmunidad Innata , Pandemias , Factores de Riesgo , /genética
7.
Med Res Rev ; 41(1): 72-135, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32852058

RESUMEN

Coronaviruses (CoVs) infect both humans and animals. In humans, CoVs can cause respiratory, kidney, heart, brain, and intestinal infections that can range from mild to lethal. Since the start of the 21st century, three ß-coronaviruses have crossed the species barrier to infect humans: severe-acute respiratory syndrome (SARS)-CoV-1, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV-2 (2019-nCoV). These viruses are dangerous and can easily be transmitted from human to human. Therefore, the development of anticoronaviral therapies is urgently needed. However, to date, no approved vaccines or drugs against CoV infections are available. In this review, we focus on the medicinal chemistry efforts toward the development of antiviral agents against SARS-CoV-1, MERS-CoV, SARS-CoV-2, targeting biochemical events important for viral replication and its life cycle. These targets include the spike glycoprotein and its host-receptors for viral entry, proteases that are essential for cleaving polyproteins to produce functional proteins, and RNA-dependent RNA polymerase for viral RNA replication.


Asunto(s)
/epidemiología , Química Farmacéutica , Brotes de Enfermedades , Antivirales/química , Antivirales/farmacología , Reposicionamiento de Medicamentos , Humanos , Internalización del Virus/efectos de los fármacos
8.
Bioorg Med Chem Lett ; 31: 127667, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33160024

RESUMEN

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) continues to spread worldwide, with 25 million confirmed cases and 800 thousand deaths. Effective treatments to target SARS-CoV-2 are urgently needed. In the present study, we have identified a class of cyclic sulfonamide derivatives as novel SARS-CoV-2 inhibitors. Compound 13c of the synthesized compounds exhibited robust inhibitory activity (IC50 = 0.88 µM) against SARS-CoV-2 without cytotoxicity (CC50 > 25 µM), with a selectivity index (SI) of 30.7. In addition, compound 13c exhibited high oral bioavailability (77%) and metabolic stability with good safety profiles in hERG and cytotoxicity studies. The present study identified that cyclic sulfonamide derivatives are a promising new template for the development of anti-SARS-CoV-2 agents.


Asunto(s)
Antivirales/farmacología , Descubrimiento de Drogas , Sulfonamidas/farmacología , Animales , Antivirales/síntesis química , Antivirales/química , Línea Celular , Chlorocebus aethiops , Cricetulus , Perros , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química
9.
Eur J Pharmacol ; 890: 173720, 2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33160938

RESUMEN

COVID-19 has intensified into a global pandemic with over a million deaths worldwide. Experimental research analyses have been implemented and executed with the sole rationale to counteract SARS-CoV-2, which has initiated potent therapeutic strategy development in coherence with computational biology validation focusing on the characterized viral drug targets signified by proteomic and genomic data. Spike glycoprotein is one of such potential drug target that promotes viral attachment to the host cellular membrane by binding to its receptor ACE-2 via its Receptor-Binding Domain (RBD). Multiple Sequence alignment and relative phylogenetic analysis revealed significant sequential disparities of SARS-CoV-2 as compared to previously encountered SARS-CoV and MERS-CoV strains. We implemented a drug re-purposing approach wherein the inhibitory efficacy of a cluster of thirty known drug candidates comprising of antivirals, antibiotics and phytochemicals (selection contingent on their present developmental status in underway clinical trials) was elucidated by subjecting them to molecular docking analyses against the spike protein RBD model (developed using homology modelling and validated using SAVES server 5.0) and the composite trimeric structures of spike glycoprotein of SARS-CoV-2. Our results indicated that Camostat, Favipiravir, Tenofovir, Raltegravir and Stavudine showed significant interactions with spike RBD of SARS-CoV-2. Proficient bioavailability coupled with no predicted in silico toxicity rendered them as prospective alternatives for designing and development of novel combinatorial therapy formulations for improving existing treatment regimes to combat COVID-19.


Asunto(s)
Antivirales/farmacología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Amidas/farmacología , Antibacterianos/farmacología , Sitios de Unión , Reposicionamiento de Medicamentos , Gabexato/análogos & derivados , Gabexato/farmacología , Simulación del Acoplamiento Molecular , Fitoquímicos/farmacología , Unión Proteica , Pirazinas/farmacología , Raltegravir Potásico/farmacología , Estavudina/farmacología , Tenofovir/farmacología
10.
Virus Res ; 292: 198246, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-33249060

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-COV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS-COV-2 replication (EC50 range, 2.0-31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17 F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.


Asunto(s)
Antivirales/farmacología , Carbamatos/farmacología , Carbazoles/farmacología , Citocinas/antagonistas & inhibidores , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/antagonistas & inhibidores , Replicación Viral/efectos de los fármacos , Animales , Chlorocebus aethiops , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Citocinas/inmunología , Células HeLa , Humanos , Inflamación/tratamiento farmacológico , Inflamación/virología , Células Vero
11.
Eur J Pharmacol ; 891: 173759, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33249077

RESUMEN

The novel coronavirus outbreak (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents the actual greatest global public health crisis. The lack of efficacious drugs and vaccines against this viral infection created a challenge for scientific researchers in order to find effective solutions. One of the promising therapeutic approaches is the search for bioactive molecules with few side effects that display antiviral properties in natural sources like medicinal plants and vegetables. Several computational and experimental studies indicated that flavonoids especially flavonols and their derivatives constitute effective viral enzyme inhibitors and possess interesting antiviral activities. In this context, the present study reviews the efficacy of many dietary flavonols as potential antiviral drugs targeting the SARS-CoV-2 enzymes and proteins including Chymotrypsin-Like Protease (3CLpro), Papain Like protease (PLpro), Spike protein (S protein) and RNA-dependent RNA polymerase (RdRp), and also their ability to interact with the angiotensin-converting enzyme II (ACE2) receptor. The relationship between flavonol structures and their SARS-CoV-2 antiviral effects were discussed. On the other hand, the immunomodulatory, the anti-inflammatory and the antiviral effects of secondary metabolites from this class of flavonoids were reported. Also, their bioavailability limitations and toxicity were predicted.


Asunto(s)
Flavonoles/farmacología , /metabolismo , Antivirales/farmacología , /metabolismo , /metabolismo , Desarrollo de Medicamentos , Humanos , Fitoquímicos/farmacología , /fisiología , Glicoproteína de la Espiga del Coronavirus/metabolismo
12.
Food Chem Toxicol ; 147: 111887, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33253764

RESUMEN

The symptoms associated with Covid-19 caused by SARS-CoV-2 in severe conditions can cause multiple organ failure and fatality via a plethora of mechanisms, and it is essential to discover the efficacious and safe drug. For this, a successful strategy is to inhibit in different stages of the SARS-CoV-2 life cycle and host cell reactions. The current review briefly put forth the summary of the SARS-CoV-2 pandemic and highlight the critical areas of understanding in genomics, proteomics, medicinal chemistry, and natural products derived drug discovery. The review further extends to briefly put forth the updates in the drug testing system, biologics, biophysics, and their advances concerning SARS-CoV-2. The salient features include information on SARS-CoV-2 morphology, genomic characterization, and pathophysiology along with important protein targets and how they influence the drug design and development against SARS-CoV-2 and a concerted and integrated approach to target these stages. The review also gives the status of drug design and discovery to identify the drugs acting on critical targets in SARS-CoV-2 and host reactions to treat Covid-19.


Asunto(s)
Antivirales/farmacología , /efectos de los fármacos , Productos Biológicos , Diseño de Fármacos , Descubrimiento de Drogas , Humanos , Pandemias , /ultraestructura
13.
Eur J Pharmacol ; 891: 173781, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33271151

RESUMEN

The coronavirus disease of 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which started in late 2019 in Wuhan, China spread to the whole world in a short period of time, and thousands of people have died due to this epidemic. Although scientists have been searching for methods to manage SARS-CoV-2, there is no specific medication against COVID-19 as of yet. Two main approaches should be followed in the treatment of SARS-CoV-2; one of which is to neutralize the virus, and the other is to inhibit the host cell membrane receptors, where SARS-CoV-2 will bind. In this study, peptides derived from beta-lactoglobulin, which inactivates both the virus and its receptors in the host cell, were identified using computer-based in silico analysis. The beta-lactoglobulin derived peptides used in this study were obtained by the treatment of goat milk whey fraction with trypsin. The structure of the peptides was characterized by the liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF/MS), and six beta-lactoglobulin derived peptides were selected as candidate peptides. Subsequently, the effects of peptides on SARS-CoV-2 and host cells were identified using virtual screening. According to the results of this in silico analysis, Ala-Leu-Pro-Met-His-Ile-Arg (ALMPHIR) and Ile-Pro-Ala-Val-Phe-Lys (IPAVFK) peptides were evaluated as potential candidates to be used in the treatment of SARS-CoV-2 after the future in vitro and in vivo studies.


Asunto(s)
Descubrimiento de Drogas/métodos , Lactoglobulinas/farmacología , Proteína de Suero de Leche/farmacología , Antivirales/farmacología , Bioprospección/métodos , /metabolismo , Simulación por Computador , Humanos , Simulación del Acoplamiento Molecular , /fisiología
14.
J Mol Graph Model ; 102: 107763, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33069124

RESUMEN

The molecular electronic density theory (MEDT) was invested to elucidate the chemo-, regio- and stereo-selectivity of the 1,3-dipolar cycloaddition between Diazomethane (DZM) and Psilostachyin (PSH). The DFT method at B3LYP/6-31 + G (d,p) level of theory was used. Reactivity indices, transition structures theory, IGM and ELF analysis were employed to reveal the mechanism of the reaction. The addition of DZM to PSH takes place through a one-step mechanism and an asynchronous transition states. Eight possible addition channels of reaction were investigated (addition of C (sp2) to Diazomethane at C4, C5, C6 or C7). The addition of C (sp2) at C5 leading to P1 product is the preferred channel. The addition of ether does not affect the chemo-, regio- and stereo-selectivity of the reaction. Analysis of transfer of charges along the IRC path associated with the P1 product shows a polar character for the studied reaction. We have also used the noncovalent interaction (NCI) which is very helpful to reveal the most favored addition channel of the reaction, by analyzing the weak interactions in different TSs. Finally, we investigate about the potential of inhibition of some pyrazoline compounds against COVID-19-Mpro by performing a molecular docking calculations.


Asunto(s)
Antivirales/química , Antivirales/farmacología , Lactonas/química , Lactonas/farmacología , /enzimología , Sesquiterpenos/química , Sesquiterpenos/farmacología , Proteínas de la Matriz Viral/química , Proteínas de la Matriz Viral/efectos de los fármacos , /tratamiento farmacológico , Reacción de Cicloadición , Diazometano/química , Humanos , Simulación del Acoplamiento Molecular , Pandemias , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Conformación Proteica , Pirazoles/química , Pirazoles/farmacología , Electricidad Estática
15.
Eur J Pharmacol ; 890: 173648, 2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33069672

RESUMEN

In an attempt to search for selective inhibitors against the SARS-CoV-2 which caused devastating of lives and livelihoods across the globe, 415 natural metabolites isolated from several plants, fungi and bacteria, belonging to different classes, were investigated. The drug metabolism and safety profiles were computed in silico and the results showed seven compounds namely fusaric acid, jasmonic acid, jasmonic acid methyl ester, putaminoxin, putaminoxin B and D, and stagonolide K were predicted to having considerable absorption, metabolism, distribution and excretion parameters (ADME) and safety indices. Molecular docking against the receptor binding domain (RBD) of spike glycoprotein (S1) and the main protease (Mpro) exposed the compounds having better binding affinity to main protease as compared to the S1 receptor binding domain. The docking results were compared to an antiviral drug penciclovir reportedly of clinical significance in treating the SARS-CoV-2 infected patients. The results demonstrated the test compounds jasmonic acid, putaminoxins B and D bound to the HIS-CYS catalytic dyad as well as to other residues within the MPro active site with much greater affinity than penciclovir. The findings of the study suggest that these compounds could be explored as potential SARS-CoV-2 inhibitors, and could further be combined with the experimental investigations to develop effective therapeutics to deal with the present pandemic.


Asunto(s)
Antivirales/farmacología , Productos Biológicos/farmacología , Fitoquímicos/farmacología , Inhibidores de Proteasas/farmacología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Antivirales/farmacocinética , Bacterias/metabolismo , Productos Biológicos/farmacocinética , Barrera Hematoencefálica/metabolismo , Ciclopentanos/farmacocinética , Ciclopentanos/farmacología , Hongos/metabolismo , Humanos , Absorción Intestinal , Lactonas/farmacocinética , Lactonas/farmacología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Oxilipinas/farmacocinética , Oxilipinas/farmacología , Fitoquímicos/farmacocinética , Plantas/metabolismo , Inhibidores de Proteasas/farmacocinética , Unión Proteica , Dominios Proteicos
16.
Eur J Pharmacol ; 890: 173701, 2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33130279

RESUMEN

The world is currently witnessing the spread of the deadly severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the coronavirus disease 2019 (COVID-19). In less than three months since the first cases were reported, the World Health Organization declared it a pandemic disease. Although several treatment and prevention strategies are currently under investigation, a continuous effort to investigate and develop effective cures is urgently needed. Thus, we performed molecular docking and structure-based virtual screening of libraries of approved drugs, antivirals, inhibitors of protein-protein interactions, and one million other small molecules to identify strong binders of the SARS-CoV-2 receptor-binding domain (RBD) that might interfere with the receptor recognition process, so as to inhibit the viral cellular entry. According to our screening and selection criteria, three approved antivirals (elbasvir, grazoprevir, and sovaprevir) and 4 other drugs (hesperidin, pamaqueside, diosmin, and sitogluside) were identified as potent binders of the RBD. The binding of these molecules involved several RBD residues required for the interaction of the virus with its cellular receptor. Furthermore, this study also discussed the pharmacological action of the 4 non-antiviral drugs on hematological and neurological disorders that, in addition to inhibiting the viral entry, could be beneficial against the neurological disorders identified in COVID-19 patients. Besides, six other small-molecules were identified, with no pharmacological description so far, exhibiting strong binding affinities to the RBD that we believe worth being investigated as inhibitors of the SARS-CoV-2-receptor interaction.


Asunto(s)
Antivirales/farmacología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Ligandos , Simulación del Acoplamiento Molecular , Unión Proteica , Dominios Proteicos , Glicoproteína de la Espiga del Coronavirus/química
17.
Eur J Pharmacol ; 890: 173688, 2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33130280

RESUMEN

The coronavirus disease-19 (COVID-19) outbreak that is caused by a highly contagious severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a zoonotic pandemic, with approximately 24.5 million positive cases and 8.3 lakhs deaths globally. The lack of effective drugs or vaccine provoked the research for drug candidates that can disrupt the spread and progression of the virus. The identification of drug molecules through experimental studies is time-consuming and expensive, so there is a need for developing alternative strategies like in silico approaches which can yield better outcomes in less time. Herein, we selected transmembrane protease serine 2 (TMPRSS2) enzyme, a potential pharmacological target against SARS-CoV-2, involved in the spread and pathogenesis of the virus. Since 3D structure is not available for this protein, the present study aims at homology modelling and validation of TMPRSS2 using Swiss-model server. Validation of the modelled TMPRSS2 using various online tools confirmed model accuracy, topology and stereochemical plausibility. The catalytic triad consisting of Serine-441, Histidine-296 and Aspartic acid-345 was identified as active binding site of TMPRSS2 using existing ligands. Molecular docking studies of various drugs and phytochemicals against the modelled TMPRSS2 were performed using camostat as a standard drug. The results revealed eight potential drug candidates, namely nafamostat, meloxicam, ganodermanontriol, columbin, myricetin, proanthocyanidin A2, jatrorrhizine and baicalein, which were further studied for ADME/T properties. In conclusion, the study unravelled eight high affinity binding compounds, which may serve as potent antagonists against TMPRSS2 to impact COVID-19 drug therapy.


Asunto(s)
Antivirales/farmacología , Modelos Moleculares , Serina Endopeptidasas/metabolismo , Inhibidores de Serina Proteinasa/farmacología , Berberina/análogos & derivados , Berberina/farmacología , Sitios de Unión , Diterpenos/farmacología , Flavanonas/farmacología , Flavonoides/farmacología , Guanidinas/farmacología , Lactonas/farmacología , Lanosterol/análogos & derivados , Lanosterol/farmacología , Meloxicam/farmacología , Proantocianidinas/farmacología , Unión Proteica
18.
Eur J Pharmacol ; 890: 173664, 2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-33131721

RESUMEN

Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) Main protease (Mpro) is one of the vital drug targets amongst all the coronaviruses, as the protein is indispensable for virus replication. The study aimed to identify promising lead molecules against Mpro enzyme through virtual screening of Malaria Venture (MMV) Malaria Box (MB) comprising of 400 experimentally proven compounds. The binding affinities were studied using virtual screening based molecular docking, which revealed five molecules having the highest affinity scores compared to the reference molecules. Utilizing the established 3D structure of Mpro the binding affinity conformations of the docked complexes were studied by Molecular Dynamics (MD) simulations. The MD simulation trajectories were analysed to monitor protein deviation, relative fluctuation, atomic gyration, compactness covariance, residue-residue map and free energy landscapes. Based on the present study outcome, we propose three Malaria_box (MB) compounds, namely, MB_241, MB_250 and MB_266 to be the best lead compounds against Mpro activity. The compounds may be evaluated for their inhibitory activities using experimental techniques.


Asunto(s)
Antivirales/farmacología , Inhibidores de Proteasas/farmacología , Antivirales/uso terapéutico , /metabolismo , Bases de Datos Factuales , Descubrimiento de Drogas , Humanos , Malaria/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Inhibidores de Proteasas/uso terapéutico
19.
Angew Chem Int Ed Engl ; 60(1): 432-438, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-32939952

RESUMEN

The COVID-19 pandemic caused by SARS-CoV-2 has become a global threat. Understanding the underlying mechanisms and developing innovative treatments are extremely urgent. G-quadruplexes (G4s) are important noncanonical nucleic acid structures with distinct biofunctions. Four putative G4-forming sequences (PQSs) in the SARS-CoV-2 genome were studied. One of them (RG-1), which locates in the coding sequence region of SARS-CoV-2 nucleocapsid phosphoprotein (N), has been verified to form a stable RNA G4 structure in live cells. G4-specific compounds, such as PDP (pyridostatin derivative), can stabilize RG-1 G4 and significantly reduce the protein levels of SARS-CoV-2 N by inhibiting its translation both in vitro and in vivo. This result is the first evidence that PQSs in SARS-CoV-2 can form G4 structures in live cells, and that their biofunctions can be regulated by a G4-specific stabilizer. This finding will provide new insights into developing novel antiviral drugs against COVID-19.


Asunto(s)
Antivirales/farmacología , G-Cuádruplex/efectos de los fármacos , ARN Viral/efectos de los fármacos , /efectos de los fármacos , Evaluación Preclínica de Medicamentos , Regulación Viral de la Expresión Génica/efectos de los fármacos , Genoma Viral , Humanos , Proteínas de la Nucleocápside/química , Proteínas de la Nucleocápside/efectos de los fármacos , Pliegue de Proteína , Bibliotecas de Moléculas Pequeñas , Temperatura
20.
Trends Parasitol ; 37(1): 48-64, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33189582

RESUMEN

Here we tell the story of ivermectin, describing its anthelmintic and insecticidal actions and recent studies that have sought to reposition ivermectin for the treatment of other diseases that are not caused by helminth and insect parasites. The standard theory of its anthelmintic and insecticidal mode of action is that it is a selective positive allosteric modulator of glutamate-gated chloride channels found in nematodes and insects. At higher concentrations, ivermectin also acts as an allosteric modulator of ion channels found in host central nervous systems. In addition, in tissue culture, at concentrations higher than anthelmintic concentrations, ivermectin shows antiviral, antimalarial, antimetabolic, and anticancer effects. Caution is required before extrapolating from these preliminary repositioning experiments to clinical use, particularly for Covid-19 treatment, because of the high concentrations of ivermectin used in tissue-culture experiments.


Asunto(s)
Antihelmínticos/farmacología , Insecticidas/farmacología , Ivermectina/farmacología , Animales , Antimaláricos/farmacología , Antineoplásicos/farmacología , Antivirales/farmacología , Línea Celular , Canales de Cloruro/efectos de los fármacos , Virus del Dengue/efectos de los fármacos , Canales Iónicos/efectos de los fármacos , Nematodos/efectos de los fármacos , /efectos de los fármacos
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