Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 54.819
Filtrar
1.
Biochem J ; 478(1): 157-177, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33439990

RESUMO

Since late 2019, biomedical labs all over the world have been struggling to cope with the 'new normal' and to find ways in which they can contribute to the fight against COVID-19. In this unique situation where a biomedical issue dominates people's lives and the news cycle, chemical biology has a great deal to contribute. This review will describe the importance of science at the chemistry/biology interface to both understand and combat the SARS-CoV-2 pandemic.


Assuntos
Antivirais/química , /fisiologia , Animais , Antivirais/farmacologia , Desenho de Fármacos , Descoberta de Drogas , Humanos , /genética
2.
Sci Data ; 8(1): 16, 2021 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441564

RESUMO

Our systematic literature collection and annotation identified 106 chemical drugs and 31 antibodies effective against the infection of at least one human coronavirus (including SARS-CoV, SAR-CoV-2, and MERS-CoV) in vitro or in vivo in an experimental or clinical setting. A total of 163 drug protein targets were identified, and 125 biological processes involving the drug targets were significantly enriched based on a Gene Ontology (GO) enrichment analysis. The Coronavirus Infectious Disease Ontology (CIDO) was used as an ontological platform to represent the anti-coronaviral drugs, chemical compounds, drug targets, biological processes, viruses, and the relations among these entities. In addition to new term generation, CIDO also adopted various terms from existing ontologies and developed new relations and axioms to semantically represent our annotated knowledge. The CIDO knowledgebase was systematically analyzed for scientific insights. To support rational drug design, a "Host-coronavirus interaction (HCI) checkpoint cocktail" strategy was proposed to interrupt the important checkpoints in the dynamic HCI network, and ontologies would greatly support the design process with interoperable knowledge representation and reasoning.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Conjuntos de Dados como Assunto , Desenho de Fármacos , Humanos , Bases de Conhecimento , Coronavírus da Síndrome Respiratória do Oriente Médio , Vírus da SARS
3.
Pestic Biochem Physiol ; 171: 104740, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33357562

RESUMO

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.


Assuntos
Antivirais , Vírus do Mosaico do Tabaco , Antivirais/farmacologia , Desenho de Fármacos , Oxidiazóis , Pirazóis/farmacologia , Relação Estrutura-Atividade , Sulfetos
4.
Gene ; 771: 145368, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33346100

RESUMO

Coronavirus disease-2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has become an immense threat to global public health. In this study, we performed complete genome sequencing of a SARS-CoV-2 isolate. More than 67,000 genome sequences were further inspected from Global Initiative on Sharing All Influenza Data (GISAID). Using several in silico techniques, we proposed prospective therapeutics against this virus. Through meticulous analysis, several conserved and therapeutically suitable regions of SARS-CoV-2 such as RNA-dependent RNA polymerase (RdRp), Spike (S) and Membrane glycoprotein (M) coding genes were selected. Both S and M were chosen for the development of a chimeric vaccine that can generate memory B and T cells. siRNAs were also designed for S and M gene silencing. Moreover, six new drug candidates were suggested that might inhibit the activity of RdRp. Since SARS-CoV-2 and SARS-CoV-1 have 82.30% sequence identity, a Gene Expression Omnibus (GEO) dataset of Severe Acute Respiratory Syndrome (SARS) patients were analyzed. In this analysis, 13 immunoregulatory genes were found that can be used to develop type 1 interferon (IFN) based therapy. The proposed vaccine, siRNAs, drugs and IFN based analysis of this study will accelerate the development of new treatments.


Assuntos
Antivirais/farmacologia , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Sequenciamento Completo do Genoma/métodos , Antivirais/uso terapêutico , Simulação por Computador , Sequência Conservada , Desenho de Fármacos , Feminino , Regulação Viral da Expressão Gênica/efeitos dos fármacos , Humanos , Interferons/farmacologia , Pessoa de Meia-Idade , Estudos Prospectivos , /classificação , Análise de Sequência de RNA , Glicoproteína da Espícula de Coronavírus/genética
5.
Biochim Biophys Acta Gen Subj ; 1865(1): 129773, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33132199

RESUMO

BACKGROUND: Quinazolines 1 to 6, with an aromatic or aryl-vinyl substituent in position 2 are selected with the aim to compare their structures and biological activity. The selection includes a natural alkaloid, schizocommunin, and the synthetic 2-(2'-quinolyl)-3H-quinazolin-4-one, known to interact with guanine-quadruplex dependent enzymes, respectively telomerase and topoisomerase. METHODS: Breast cancer cells of the MDA cell line have been used to study the bioactivity of the tested compounds by the method of Comet Assay and FACS analyses. We model observed effects assuming stacking interactions of studied heterocycles with a naked skeleton of G-quadruplex, consisting of guanine quartet layers and potassium ions. Interaction energies are computed using a dispersion corrected density functional theory method, and an electron-correlated molecular orbital theory method. RESULTS: Selected compounds do not remarkably delay nor change the dynamics of cellular progression through the cell cycle phases, while changing significantly cell morphology. Our computational models quantify structural effects on heterocyclic G4-complex stabilization energies, which directly correlate with observed biological activity. CONCLUSION: Our computational model of G-quadruplexes is an acceptable tool for the study of interaction energies of G-quadruplexes and heterocyclic ligands, predicting, and allowing design of novel structures. GENERAL SIGNIFICANCE: Genotoxicity of quinazolin-4-one analogues on human breast cancer cells is not related to molecular metabolism but rather to their interference with G-quadruplex regulatory mechanisms. Computed stabilization energies of heterocyclic ligand complexes of G-quadruplexes might be useful in the prediction of novel telomerase / helicase, topoisomerase and NA polymerase dependent drugs.


Assuntos
Quadruplex G/efeitos dos fármacos , Quinazolinas/química , Quinazolinas/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Descoberta de Drogas , Humanos , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Quinazolinonas/química , Quinazolinonas/farmacologia , Telômero/química
6.
J Med Chem ; 64(1): 782-796, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33356231

RESUMO

Nucleotide analogues are used for treating viral infections such as HIV, hepatitis B, hepatitis C, influenza, and SARS-CoV-2. To become polymerase substrates, a nucleotide analogue must be phosphorylated by cellular kinases which is rate-limiting. The goal of this study is to develop dNTP/NTP analogues directly from nucleotides. Tenofovir (TFV) analogues were synthesized by conjugating with amino acids. We demonstrate that some conjugates act as dNTP analogues and HIV-1 reverse transcriptase (RT) catalytically incorporates the TFV part as the chain terminator. X-ray structures in complex with HIV-1 RT/dsDNA showed binding of the conjugates at the polymerase active site, however, in different modes in the presence of Mg2+ versus Mn2+ ions. The adaptability of the compounds is seemingly essential for catalytic incorporation of TFV by RT. 4d with a carboxyl sidechain demonstrated the highest incorporation. 4e showed weak incorporation and rather behaved as a dNTP-competitive inhibitor. This result advocates the feasibility of designing NTP/dNTP analogues by chemical substitutions to nucleotide analogues.


Assuntos
Aminoácidos/química , Nucleotídeos/química , Tenofovir/química , Viroses/tratamento farmacológico , Sítios de Ligação , /virologia , Domínio Catalítico , Desenho de Fármacos , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Magnésio/química , Simulação de Acoplamento Molecular , Nucleotídeos/metabolismo , Fosforilação , Especificidade por Substrato , Viroses/virologia
7.
J Med Chem ; 64(1): 890-904, 2021 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-33372782

RESUMO

The sigma 1 receptor (S1R) is a molecular chaperone protein located in the endoplasmic reticulum and plasma membranes and has been shown to play important roles in various pathological disorders including pain and, as recently discovered, COVID-19. Employing structure- and QSAR-based drug design strategies, we rationally designed, synthesized, and biologically evaluated a series of novel triazole-based S1R antagonists. Compound 10 exhibited potent binding affinity for S1R, high selectivity over S2R and 87 other human targets, acceptable in vitro metabolic stability, slow clearance in liver microsomes, and excellent blood-brain barrier permeability in rats. Further in vivo studies in rats showed that 10 exhibited negligible acute toxicity in the rotarod test and statistically significant analgesic effects in the formalin test for acute inflammatory pain and paclitaxel-induced neuropathic pain models during cancer chemotherapy. These encouraging results promote further development of our triazole-based S1R antagonists as novel treatments for pain of different etiologies.


Assuntos
Manejo da Dor/métodos , Receptores sigma/antagonistas & inibidores , Triazóis/química , Animais , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Desenho de Fármacos , Cobaias , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Simulação de Dinâmica Molecular , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Estrutura Terciária de Proteína , Relação Quantitativa Estrutura-Atividade , Ratos , Receptores sigma/metabolismo , Triazóis/metabolismo , Triazóis/uso terapêutico
8.
Mar Drugs ; 18(12)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33322052

RESUMO

The investigation of marine natural products (MNPs) as key resources for the discovery of drugs to mitigate the COVID-19 pandemic is a developing field. In this work, computer-aided drug design (CADD) approaches comprising ligand- and structure-based methods were explored for predicting SARS-CoV-2 main protease (Mpro) inhibitors. The CADD ligand-based method used a quantitative structure-activity relationship (QSAR) classification model that was built using 5276 organic molecules extracted from the ChEMBL database with SARS-CoV-2 screening data. The best model achieved an overall predictive accuracy of up to 67% for an external and internal validation using test and training sets. Moreover, based on the best QSAR model, a virtual screening campaign was carried out using 11,162 MNPs retrieved from the Reaxys® database, 7 in-house MNPs obtained from marine-derived actinomycetes by the team, and 14 MNPs that are currently in the clinical pipeline. All the MNPs from the virtual screening libraries that were predicted as belonging to class A were selected for the CADD structure-based method. In the CADD structure-based approach, the 494 MNPs selected by the QSAR approach were screened by molecular docking against Mpro enzyme. A list of virtual screening hits comprising fifteen MNPs was assented by establishing several limits in this CADD approach, and five MNPs were proposed as the most promising marine drug-like leads as SARS-CoV-2 Mpro inhibitors, a benzo[f]pyrano[4,3-b]chromene, notoamide I, emindole SB beta-mannoside, and two bromoindole derivatives.


Assuntos
Organismos Aquáticos/química , Produtos Biológicos/farmacologia , /antagonistas & inibidores , Desenho de Fármacos , Produtos Biológicos/uso terapêutico , /virologia , Desenho Assistido por Computador , Humanos , Simulação de Acoplamento Molecular , /metabolismo
9.
J Am Chem Soc ; 142(52): 21883-21890, 2020 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-33320670

RESUMO

The SARS coronavirus 2 (SARS-CoV-2) main protease (Mpro) is an attractive broad-spectrum antiviral drug target. Despite the enormous progress in structure elucidation, the Mpro's structure-function relationship remains poorly understood. Recently, a peptidomimetic inhibitor has entered clinical trial; however, small-molecule orally available antiviral drugs have yet to be developed. Intrigued by a long-standing controversy regarding the existence of an inactive state, we explored the proton-coupled dynamics of the Mpros of SARS-CoV-2 and the closely related SARS-CoV using a newly developed continuous constant pH molecular dynamics (MD) method and microsecond fixed-charge all-atom MD simulations. Our data supports a general base mechanism for Mpro's proteolytic function. The simulations revealed that protonation of His172 alters a conserved interaction network that upholds the oxyanion loop, leading to a partial collapse of the conserved S1 pocket, consistent with the first and controversial crystal structure of SARS-CoV Mpro determined at pH 6. Interestingly, a natural flavonoid binds SARS-CoV-2 Mpro in the close proximity to a conserved cysteine (Cys44), which is hyper-reactive according to the CpHMD titration. This finding offers an exciting new opportunity for small-molecule targeted covalent inhibitor design. Our work represents a first step toward the mechanistic understanding of the proton-coupled structure-dynamics-function relationship of CoV Mpros; the proposed strategy of designing small-molecule covalent inhibitors may help accelerate the development of orally available broad-spectrum antiviral drugs to stop the current pandemic and prevent future outbreaks.


Assuntos
Antivirais/química , Antivirais/farmacologia , /efeitos dos fármacos , /enzimologia , Sítios de Ligação , Cisteína/química , Desenho de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Modelos Moleculares , Simulação de Dinâmica Molecular , Inibidores de Proteases/farmacologia , Conformação Proteica , Prótons , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade
10.
PLoS One ; 15(12): e0239112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382708

RESUMO

Influenza virus A is a significant agent involved in the outbreak of worldwide epidemics, causing millions of fatalities around the world by respiratory diseases and seasonal illness. Many projects had been conducting to investigate recovered infected patients for therapeutic vaccines that have broad-spectrum activity. With the aid of the computational approach in biology, the designation for a vaccine model is more accessible. We developed an in silico protocol called iBRAB to design a broad-reactive Fab on a wide range of influenza A virus. The Fab model was constructed based on sequences and structures of available broad-spectrum Abs or Fabs against a wide range of H1N1 influenza A virus. As a result, the proposed Fab model followed iBRAB has good binding affinity over 27 selected HA of different strains of H1 influenza A virus, including wild-type and mutated ones. The examination also took by computational tools to fasten the procedure. This protocol could be applied for a fast-designed therapeutic vaccine against different types of threats.


Assuntos
Anticorpos Antivirais/química , Antígenos Virais/química , Desenho de Fármacos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Fragmentos Fab das Imunoglobulinas/química , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/prevenção & controle , Sequência de Aminoácidos , Anticorpos Antivirais/genética , Antígenos Virais/genética , Antígenos Virais/imunologia , Sítios de Ligação , Simulação por Computador , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Fragmentos Fab das Imunoglobulinas/genética , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/biossíntese , Influenza Humana/imunologia , Influenza Humana/virologia , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Termodinâmica
11.
ACS Chem Neurosci ; 11(22): 3701-3703, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33140636

RESUMO

Cell entry, the fundamental step in cross-species transmission of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), is initiated by the recognition of the host cell angiotensin-converting enzyme-2 (ACE2) receptor by the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2. To date, several peptides have been proposed against SARS-CoV-2 both as inhibitor agents or as detection tools that can also be attached to the surfaces of nanoparticle carriers. But owing to their natural amino acid sequences, such peptides cannot be considered as efficient therapeutic candidates from a biostability point of view. This discussion demonstrates the design strategy of synthetic nonprotein amino acid substituted peptides with enhanced biostability and binding affinity, the implication of which can make those peptides potential therapeutic agents for inhibition and simple detection tools.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Desenho de Fármacos , Fragmentos de Peptídeos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Sequência de Aminoácidos , Antivirais/metabolismo , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/genética , Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Humanos , Pandemias , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Ligação Proteica/fisiologia , Análise de Sequência de Proteína/métodos
12.
Yakugaku Zasshi ; 140(11): 1305-1312, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33132265

RESUMO

Recently, biologics including peptides, proteins, antibodies, and nucleic acids have attracted interest as drug candidates for new modalities, since these compounds can act on target molecules that are not be affected by conventional drugs with a small molecular weight to promote greater selectivity, potency, and safety. Generally, to administer biologics, parenteral routes like intravenous and intramuscular injections have been mainly selected due to their poor oral absorbability and stability in the gastrointestinal tract, which can adversely affect patient compliance. Depending on the target diseases, inhalable formulations can be used to achieve both topical effects in the respiratory tracts and systemic actions due to the characteristics of the pulmonary site, including a large surface area, abundant capillary network, thin membrane with adequate permeability for macromolecules, reduced enzymatic degradation, and a lack of first-pass metabolism. In this study, to achieve desirable delivery of peptide drugs with an inhalable formulation to target sites in the respiratory tract and/or absorption sites in the lung, peptide-loaded inhalable formulations were designed by the application of flash nanoprecipitation, one of the precipitation methods to prepare functional nanoparticles, and the fine droplet drying process, a powderization technique using printing technology, to control the pharmacokinetic behavior. From the findings of the study, the strategic applications of these techniques could contribute to provide peptide-loaded inhalable formulations to enhance their biopharmaceutical potentials.


Assuntos
Produtos Biológicos/administração & dosagem , Produtos Biológicos/farmacocinética , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Peptídeos/administração & dosagem , Peptídeos/farmacocinética , Precipitação Química , Inaladores de Pó Seco , Nanopartículas
13.
J Oleo Sci ; 69(11): 1389-1401, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33132278

RESUMO

The oral route is the most prevalent route of drug administration among various routes. Dapagliflozin is an oral hypoglycemic drug used for lowering the blood glucose level. The objective of this work is to developed and optimized dapagliflozin loaded nanostructured lipid carriers (DG-NLCs) for the improvement of oral delivery. DG-NLCs were prepared by a high-pressure homogenization method (hot) and optimized by Box-Behnken design software using lipid, surfactant, and homogenization cycle as an independent variable. DG-NLCs were evaluated for particle size (Y1), entrapment efficiency (Y2), drug release (Y3). The DG-NLCs were further evaluated for morphology, thermal and X-ray diffraction analysis, ex-vivo intestinal permeation, and stability study. Particle size (nm), entrapment efficiency (%) and drug release (%) of all seventeen formulations were found in the range of 113.71-356.22 nm, 60.43-96.54% and 63.44-83.62% respectively. Morphology of optimized formulation exhibited spherical in shape confirmed by transmission electron microscopy. Thermal and X-ray diffraction analysis of NLCs showed the drug was solubilized and lost the crystallinity. DG-NLCs-opt exhibited dual release pattern initial fast and later sustained-release (90.01±2.01% in 24 h) whereas DG-dispersion showed 31.54±1.87% release in 24 h. Korsmeyer-Peppas model was found to be the best fit model (R2=0.999). The DG-NLCs-opt exhibited significant-high (p < 0.05, 1.293 µg/cm2/h) flux than DG-dispersion (0.2683 µg/cm2/h). Apparent permeation coefficient of DG-NLCs-opt was found to be significantly higher (p < 0.05, 4.14×10-5 cm/min) than DG-dispersion (8.61×10-6 cm/min). The formulation showed no significant changes (p < 0.05) on six months of storage study at 25±2°C/60±5%RH. The finding concluded that quality by design (QbD) based lipid nanocarrier for oral delivery could be a promising approach of dapagliflozin for the management of diabetes.


Assuntos
Compostos Benzidrílicos , Portadores de Fármacos , Composição de Medicamentos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Glucosídeos , Hipoglicemiantes , Absorção Intestinal , Lipídeos , Nanopartículas , Nanoestruturas , Administração Oral , Compostos Benzidrílicos/química , Compostos Benzidrílicos/metabolismo , Formas de Dosagem , Portadores de Fármacos/química , Desenho de Fármacos , Estabilidade de Medicamentos , Glucosídeos/química , Glucosídeos/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Modelos Biológicos , Tamanho da Partícula
14.
Mediators Inflamm ; 2020: 8198963, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33029105

RESUMO

The novel coronavirus is not only causing respiratory problems, but it may also damage the heart, kidneys, liver, and other organs; in Wuhan, 14 to 30% of COVID-19 patients have lost their kidney function and now require either dialysis or kidney transplants. The novel coronavirus gains entry into humans by targeting the ACE2 receptor that found on lung cells, which destroy human lungs through cytokine storms, and this leads to hyperinflammation, forcing the immune cells to destroy healthy cells. This is why some COVID-19 patients need intensive care. The inflammatory chemicals released during COVID-19 infection cause the liver to produce proteins that defend the body from infections. However, these proteins can cause blood clotting, which can clog blood vessels in the heart and other organs; as a result, the organs are deprived of oxygen and nutrients which could ultimately lead to multiorgan failure and consequent progression to acute lung injury, acute respiratory distress syndrome, and often death. However, there are novel protein modification tools called the QTY code, which are similar in their structure to antibodies, which could provide a solution to excess cytokines. These synthetic proteins can be injected into the body to bind the excess cytokines created by the cytokine storm; this will eventually remove the excessive cytokines and inhibit the severe symptoms caused by the COVID-19 infection. In this review, we will focus on cytokine storm in COVID-19 patients, their impact on the body organs, and the potential treatment by QTY code-designed detergent-free chemokine receptors.


Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/terapia , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Receptores de Quimiocinas/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , Síndrome da Liberação de Citocina/imunologia , Citocinas/antagonistas & inibidores , Desenho de Fármacos , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/imunologia , Modelos Moleculares , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/imunologia , Insuficiência de Múltiplos Órgãos/terapia , Pandemias , Pneumonia Viral/terapia , Engenharia de Proteínas , Modificação Traducional de Proteínas , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo
15.
Phys Chem Chem Phys ; 22(40): 23099-23106, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33025993

RESUMO

COVID-19 has caused lockdowns all over the world in early 2020, as a global pandemic. Both theoretical and experimental efforts are seeking to find an effective treatment to suppress the virus. In silico drug design can play a vital role in identifying promising drug candidates against COVID-19. Herein, we focused on the main protease of SARS-CoV-2 that has crucial biological functions in the virus. We performed a ligand-based virtual screening followed by a docking screening for testing approved drugs and bioactive compounds listed in the DrugBank and ChEMBL databases. The top 8 docking results were advanced to all-atom MD simulations to study the relative stability of the protein-ligand interactions. MD simulations support that the catalytic residue, His41, has a neutral side chain with a protonated delta position. An absolute binding energy (ΔG) of -42 kJ mol-1 for the protein-ligand (Mpro-N3) complex has been calculated using the potential-of-mean-force (geometrical) approach. Furthermore, the relative binding energies were computed for the top docking results. Our results suggest several promising approved and bioactive inhibitors of SARS-CoV-2 Mpro as follows: a bioactive compound, ChEMBL275592, which has the best MM/GBSA binding energy; the second-best compound, montelukast, is an approved drug used in the treatment of asthma and allergic rhinitis; the third-best compound, ChEMBL288347, is a bioactive compound. Bromocriptine and saquinavir are other approved drugs that also demonstrate stability in the active site of Mpro, albeit their relative binding energies are low compared to the N3 inhibitor. This study provides useful insights into de novo protein design and novel inhibitor development, which could reduce the cost and time required for the discovery of a potent drug to combat SARS-CoV-2.


Assuntos
Betacoronavirus/enzimologia , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/metabolismo , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/metabolismo , Desenho de Fármacos , Humanos , Ligação de Hidrogênio , Ligantes , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Inibidores de Proteases/metabolismo , Eletricidade Estática , Termodinâmica , Proteínas não Estruturais Virais/metabolismo
16.
J Proteome Res ; 19(11): 4291-4315, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-33119313

RESUMO

The emergence in late 2019 of the coronavirus SARS-CoV-2 has resulted in the breakthrough of the COVID-19 pandemic that is presently affecting a growing number of countries. The development of the pandemic has also prompted an unprecedented effort of the scientific community to understand the molecular bases of the virus infection and to propose rational drug design strategies able to alleviate the serious COVID-19 morbidity. In this context, a strong synergy between the structural biophysics and molecular modeling and simulation communities has emerged, resolving at the atomistic level the crucial protein apparatus of the virus and revealing the dynamic aspects of key viral processes. In this Review, we focus on how in silico studies have contributed to the understanding of the SARS-CoV-2 infection mechanism and the proposal of novel and original agents to inhibit the viral key functioning. This Review deals with the SARS-CoV-2 spike protein, including the mode of action that this structural protein uses to entry human cells, as well as with nonstructural viral proteins, focusing the attention on the most studied proteases and also proposing alternative mechanisms involving some of its domains, such as the SARS unique domain. We demonstrate that molecular modeling and simulation represent an effective approach to gather information on key biological processes and thus guide rational molecular design strategies.


Assuntos
Antivirais , Infecções por Coronavirus , Desenho de Fármacos , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral , Glicoproteína da Espícula de Coronavírus , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Humanos , Simulação de Dinâmica Molecular , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Internalização do Vírus
17.
PLoS One ; 15(10): e0240079, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33022015

RESUMO

The Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) pandemic represents a global challenge. SARS-CoV-2's ability to replicate in host cells relies on the action of its non-structural proteins, like its main protease (Mpro). This cysteine protease acts by processing the viruses' precursor polyproteins. As proteases, together with polymerases, are main targets of antiviral drug design, we here have performed biochemical high throughput screening (HTS) with recombinantly expressed SARS-CoV-2 Mpro. A fluorescent assay was used to identify inhibitors in a compound library containing known drugs, bioactive molecules and natural products. These screens led to the identification of 13 inhibitors with IC50 values ranging from 0.2 µM to 23 µM. The screens confirmed several known SARS-CoV Mpro inhibitors as inhibitors of SARS-CoV-2 Mpro, such as the organo-mercuric compounds thimerosal and phenylmercuric acetate. Benzophenone derivatives could also be identified among the most potent screening hits. Additionally, Evans blue, a sulfonic acid-containing dye, could be identified as an Mpro inhibitor. The obtained compounds could be of interest as lead compounds for the development of future SARS-CoV-2 drugs.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Infecções por Coronavirus/virologia , Avaliação Pré-Clínica de Medicamentos/métodos , Pneumonia Viral/virologia , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Cisteína Endopeptidases/química , Desenho de Fármacos , Escherichia coli/genética , Concentração Inibidora 50 , Modelos Moleculares , Pandemias , Proteínas não Estruturais Virais/química
18.
Nat Commun ; 11(1): 5047, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028810

RESUMO

COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.


Assuntos
Betacoronavirus/química , Cisteína Endopeptidases/química , Fragmentos de Peptídeos/química , Proteínas não Estruturais Virais/química , Betacoronavirus/enzimologia , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Cisteína Endopeptidases/metabolismo , Desenho de Fármacos , Espectrometria de Massas , Modelos Moleculares , Fragmentos de Peptídeos/metabolismo , Conformação Proteica , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Eletricidade Estática , Proteínas não Estruturais Virais/metabolismo
19.
Molecules ; 25(20)2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33050240

RESUMO

Studying disease models at the molecular level is vital for drug development in order to improve treatment and prevent a wide range of human pathologies. Microbial infections are still a major challenge because pathogens rapidly and continually evolve developing drug resistance. Cancer cells also change genetically, and current therapeutic techniques may be (or may become) ineffective in many cases. The pathology of many neurological diseases remains an enigma, and the exact etiology and underlying mechanisms are still largely unknown. Viral infections spread and develop much more quickly than does the corresponding research needed to prevent and combat these infections; the present and most relevant outbreak of SARS-CoV-2, which originated in Wuhan, China, illustrates the critical and immediate need to improve drug design and development techniques. Modern day drug discovery is a time-consuming, expensive process. Each new drug takes in excess of 10 years to develop and costs on average more than a billion US dollars. This demonstrates the need of a complete redesign or novel strategies. Nuclear Magnetic Resonance (NMR) has played a critical role in drug discovery ever since its introduction several decades ago. In just three decades, NMR has become a "gold standard" platform technology in medical and pharmacology studies. In this review, we present the major applications of NMR spectroscopy in medical drug discovery and development. The basic concepts, theories, and applications of the most commonly used NMR techniques are presented. We also summarize the advantages and limitations of the primary NMR methods in drug development.


Assuntos
Desenho de Fármacos , Descoberta de Drogas/métodos , Espectroscopia de Ressonância Magnética/métodos , Humanos
20.
Mar Drugs ; 18(10)2020 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-33081023

RESUMO

Labdane diterpenes are widespread classes of natural compounds present in variety of marine and terrestrial organisms and plants. Many of them represents "natural libraries" of compounds with interesting biological activities due to differently functionalized drimane nucleus exploitable for potential pharmacological applications. The transient receptor potential channel subfamily V member 4 (TRPV4) channel has recently emerged as a pharmacological target for several respiratory diseases, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inspired by the labdane-like bicyclic core, a series of homodrimane-derived esters and amides was designed and synthesized by modifying the flexible tail in position 1 of (+)-sclareolide, an oxidized derivative of the bioactive labdane-type diterpene sclareol. The potency and selectivity towards rTRPV4 and hTRPV1 receptors were assessed by calcium influx cellular assays. Molecular determinants critical for eliciting TRPV4 antagonism were identified by structure-activity relationships. Among the selective TRPV4 antagonists identified, compound 6 was the most active with an IC50 of 5.3 µM. This study represents the first report of semisynthetic homodrimane TRPV4 antagonists, selective over TRPV1, and potentially useful as pharmacological tools for the development of novel TRPV4 channel modulators.


Assuntos
Diterpenos/síntese química , Diterpenos/farmacologia , Desenho de Fármacos , Canais de Cátion TRPV/antagonistas & inibidores , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA