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1.
Life Sci ; 264: 118621, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33164832

RESUMO

AIMS: Protein tyrosine phosphatase (PTP-CPS4B) is a signaling enzyme that is essential for a wide range of cellular processes, like metabolism, proliferation, survival and motility. Studies suggest that PTPs are vital for the production of Wzy-dependent capsule in bacteria, making it a valuable target for the discovery of pneumonia associated anti-virulence antibacterial agents. Present study aims at identifying the potential drug candidates to be exploited in inhibiting the growth of Streptococcus pneumonia targeting PTP-CPS4B. MATERIALS AND METHODS: The present study exploits the molecular docking potential coupled with molecular dynamic simulation as well as free energy calculations to identify potential inhibitors of PTP-CPS4B. Libraries of known and unknown compounds were docked into the active site of PTP-CPS4B using MOE. The compounds with best binding affinity and orientation were subjected to MD simulations and free energy calculations. FINDINGS: Top three compounds based on their binding energy and well composed interaction pattern obtained from molecular docking study were subjected to MD simulations and were compared to reported antibiotic drugs. MD Simulation studies have shown that the presence of an inhibitor inside the active site reduces protein flexibility as evident from RMSD, RMSF and Principal component analyses. MD simulations identified a transition from extended to bended motional shift in loop α6 of the PTP-CPS4B in ligand bound state. This flexibility was reported in the RMSF analysis and verified by the visual investigation of the loop α6 at different time intervals during the simulation. Free energy of binding affinity (computed using MMPBSA &MMGBSA approach) and the interaction patterns obtained from MD trajectory indicate that compound ZN1 (-31.50 Kcal/mol), ZN2 (-33.14 Kcal/mol) and ZN3 (-26.60 Kcal/mol) are potential drug candidates against PTP-CPS4B. Residue wise decomposition study helped in identifying the role of individual amino acid towards the overall inhibition behavior of the compounds. PCA analysis has led to the conclusion that the behavior of PTP-CPS4B inhibitors causes conformational dynamics that can be used to describe the protein inhibition mechanism. SIGNIFICANCE: The outcome reveals that this study provide enough evidences for the consideration of ZN1, ZN2, ZN3 as potential PTP-CPS4B inhibitors and further in vitro and in vivo studies may prove their therapeutic potential.


Assuntos
Antibacterianos/química , Proteínas de Bactérias/química , Proteínas Tirosina Fosfatases/química , Streptococcus pneumoniae/efeitos dos fármacos , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Domínio Catalítico , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ligação de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Termodinâmica
2.
Mol Inform ; 40(1): e2000144, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830452

RESUMO

The analysis of B-factor profiles from X-ray protein structures can be utilized for structure-based drug design since protein mobility changes have been associated with the quality of protein-ligand interactions. With the BANΔIT (B'-factor analysis and ΔB' interpretation toolkit), we have developed a JavaScript-based browser application that provides a graphical user interface for the normalization and analysis of B'-factor profiles. To emphasize the usability for rational drug design applications, we have analyzed a selection of crystallographic protein-ligand complexes and have given exemplary conclusions for further drug optimization including the development of a B'-factor-supported pharmacophore model for SARS CoV-2 main protease inhibitors. BANΔIT is available online at https://bandit.uni-mainz.de. The source code can be downloaded from https://github.com/FBarthels/BANDIT.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Desenho de Fármacos , Inibidores de Proteases/química , Navegador , Monofosfato de Adenosina/química , Monofosfato de Adenosina/uso terapêutico , Biologia Computacional , Humanos , Inibidores de Proteases/uso terapêutico
3.
Food Chem Toxicol ; 147: 111887, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33253764

RESUMO

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.


Assuntos
Antivirais/farmacologia , /efeitos dos fármacos , Produtos Biológicos , Desenho de Fármacos , Descoberta de Drogas , Humanos , Pandemias , /ultraestrutura
4.
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
5.
Toxicol Lett ; 337: 18-27, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33232777

RESUMO

BACKGROUND AND OBJECTIVE: Optimal experimental design theory proposes choosing specific settings in experimental trials in order to maximize the precision of the resulting parameter estimates. In dose response experiments, this corresponds to choosing the optimal dose levels for every available observation, and can be applied both to singular dose-response relationships and to interaction experiments where two substances are given simultaneously at several different mixture ratios ("ray designs"). While the theory of experimental design for this situation is well developed, the mathematical complexity prevents widespread use in practical applications. A simple to use application making the theory accessible to practitioners is thus very desirable. METHODS: Results from established optimal experimental design theory are applied to dose response applications, focusing on log-logistic and Weibull class dose response functions. Suitable optimal design algorithms to solve these problems are implemented into an R-shiny based online application. RESULTS: The application provides an interface to easily calculate D-optimal designs not only for singular dose experiments, but also for interaction trials with several combination rays of substances. Furthermore, the app also allows evaluating the efficiency of existing candidate designs, and finally allows construction of designs which perform robustly under different assumptions in regard to the true parameters.


Assuntos
Algoritmos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Interações Medicamentosas , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Humanos , Projetos de Pesquisa
7.
Chem Biol Interact ; 333: 109318, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33186599

RESUMO

Antimicrobial resistance is at increasing risk worldwide since it is threatening the ability to control common infectious diseases, resulting in prolonged illness, disability, and death. Herein, we inspired by the effective plant phytochemical mechanisms evolved to overcome microbial pathogenesis and evolved resistance. Cuminaldehyde is previously reported as the main antibacterial component in Calligonum comosum essential oil. The toxicity of cuminaldehyde limits its medical application for human use. On the other hand, compared to cuminaldehyde, the plant total extract showed similar antibacterial activities, while maintained lower toxicity, although it contains 22 times less cuminaldehyde. Thus, we assumed that other components in the plant extracts specifically affect bacteria but not mammalian cells. Bioassay-guided fractionations combined with comparative metabolomics analysis of different plant extracts were employed. The results revealed the presence of bacterial species-specific phytochemicals. Cinnamyl linoleate and linoleic acid enhanced the antibacterial activities of cuminaldehyde and ampicillin against S. aureus including MRSA, while decanal and cinnamyl linoleate enhanced the activities against E. coli. Computational modeling and enzyme inhibition assays indicated that cinnamyl linoleate selectively bind to bacterial ribosomal RNA methyltransferase, an important enzyme involved in the virulence and resistance of multidrug resistant bacteria. The results obtained can be employed for the future preparation of pharmaceutical formula containing cinnamyl linoleate in order to overcome evolved multidrug resistance behaviors by microbes.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Caryophyllales/química , Desenho de Fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Óleos Voláteis/química , Compostos Fitoquímicos/química , Antibacterianos/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Linhagem Celular , Técnicas de Química Sintética , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos
8.
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
9.
Life Sci ; 264: 118674, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33129876

RESUMO

AIMS: Arginine depleting enzymes are found effective to treat arginine-auxotrophic cancers and therapy-resistant malignancies, alone or in combination with cytotoxic agents or immune checkpoint inhibitors. We aim to select and validate a long-lasting, safe and effective PEGylated and cobalt-chelated arginase conjugated at the selective cysteine residue as a therapeutic agent against cancers. MAIN METHODS: Exploring pharmacokinetic and pharmacodynamic properties of the three arginase conjugates with different PEG modality (20 kDa linear as A20L, 20 kDa branched as A20Y, and 40 kDa branched as A40Y) by cell-based and animal studies. KEY FINDINGS: Arginase conjugates showed comparable systemic half-lives, about 20 h in rats and mice. The extended half-life of PEGylated arginase was concurrent with the integrity of conjugates of which PEG and protein moieties remain attached in bloodstream for 72 h after drug administration. Arginase modified with a linear 20 kDa PEG (A20L) was chosen as the lead candidate (PT01). In vitro assays confirmed the very potent cytotoxicity of PT01 against cancer cell lines of breast, prostate, and pancreas origin. In MIA PaCa-2 pancreatic and PC-3 prostate tumor xenograft models, weekly infusion of the PT01 at 5 and 10 mg/kg induced significant tumor growth inhibition of 44-67%. All mice experienced dose-dependent but rapidly reversible weight loss following each weekly dose, suggesting tolerable toxicity. SIGNIFICANCE: These non-clinical data support PT01 as the lead candidate for clinical development that may benefit cancer patients by providing an alternative cytotoxic mechanism.


Assuntos
Antineoplásicos/síntese química , Arginase/síntese química , Arginina/deficiência , Engenharia Química/métodos , Desenho de Fármacos , Polietilenoglicóis/síntese química , Animais , Antineoplásicos/administração & dosagem , Arginase/administração & dosagem , Arginina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/administração & dosagem , Isoenzimas/síntese química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Polietilenoglicóis/administração & dosagem , Estrutura Secundária de Proteína , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
10.
Sci Rep ; 10(1): 20808, 2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33257760

RESUMO

The COVID-19 pandemic caused by the SARS-CoV-2 requires a fast development of antiviral drugs. SARS-CoV-2 viral main protease (Mpro, also called 3C-like protease, 3CLpro) is a potential target for drug design. Crystal and co-crystal structures of the SARS-CoV-2 Mpro have been solved, enabling the rational design of inhibitory compounds. In this study we analyzed the available SARS-CoV-2 and the highly similar SARS-CoV-1 crystal structures. We identified within the active site of the Mpro, in addition to the inhibitory ligands' interaction with the catalytic C145, two key H-bond interactions with the conserved H163 and E166 residues. Both H-bond interactions are present in almost all co-crystals and are likely to occur also during the viral polypeptide cleavage process as suggested from docking of the Mpro cleavage recognition sequence. We screened in silico a library of 6900 FDA-approved drugs (ChEMBL) and filtered using these key interactions and selected 29 non-covalent compounds predicted to bind to the protease. Additional screen, using DOCKovalent was carried out on DrugBank library (11,414 experimental and approved drugs) and resulted in 6 covalent compounds. The selected compounds from both screens were tested in vitro by a protease activity inhibition assay. Two compounds showed activity at the 50 µM concentration range. Our analysis and findings can facilitate and focus the development of highly potent inhibitors against SARS-CoV-2 infection.


Assuntos
Antivirais/farmacologia , /antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Inibidores de Proteases/farmacologia , Sequência de Aminoácidos , Domínio Catalítico/efeitos dos fármacos , Desenho de Fármacos , Descoberta de Drogas , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/enzimologia , /enzimologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo
11.
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
12.
Semin Immunol ; 50: 101422, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-33262067

RESUMO

SARS-CoV-2, the virus that causes COVID-19, emerged in late 2019, and was declared a global pandemic on March 11th 2020. With over 50 million cases and 1.2 million deaths around the world, to date, this pandemic represents the gravest global health crisis of our times. Thus, the race to develop a COVID-19 vaccine is an urgent global imperative. At the time of writing, there are over 165 vaccine candidates being developed, with 33 in various stages of clinical testing. In this review, we discuss emerging insights about the human immune response to SARS-CoV-2, and their implications for vaccine design. We then review emerging knowledge of the immunogenicity of the numerous vaccine candidates that are currently being tested in the clinic and discuss the range of immune defense mechanisms that can be harnessed to develop novel vaccines that confer durable protection against SARS-CoV-2. Finally, we conclude with a discussion of the potential role of a systems vaccinology approach in accelerating the clinical testing of vaccines, to meet the urgent needs posed by the pandemic.


Assuntos
/imunologia , Desenho de Fármacos , Vacinologia/métodos , Adjuvantes Imunológicos/uso terapêutico , Adulto , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , /patologia , Modelos Animais de Doenças , Humanos , Pessoa de Meia-Idade , Biologia de Sistemas/métodos , Linfócitos T/imunologia , Adulto Jovem
13.
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
14.
Molecules ; 25(23)2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33287144

RESUMO

The RNA-dependent RNA polymerase (RdRp) is an essential enzyme for the viral replication process, catalyzing the viral RNA synthesis using a metal ion-dependent mechanism. In recent years, RdRp has emerged as an optimal target for the development of antiviral drugs, as demonstrated by recent approvals of sofosbuvir and remdesivir against Hepatitis C virus (HCV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respectively. In this work, we overview the main sequence and structural features of the RdRp of emerging RNA viruses such as Coronaviruses, Flaviviruses, and HCV, as well as inhibition strategies implemented so far. While analyzing the structural information available on the RdRp of emerging RNA viruses, we provide examples of success stories such as for HCV and SARS-CoV-2. In contrast, Flaviviruses' story has raised attention about how the lack of structural details on catalytically-competent or ligand-bound RdRp strongly hampers the application of structure-based drug design, either in repurposing and conventional approaches.


Assuntos
Antivirais/química , Antivirais/farmacologia , Vírus de RNA/enzimologia , /química , Amidas/química , Amidas/farmacologia , Coronavirus/efeitos dos fármacos , Coronavirus/enzimologia , Coronavirus/genética , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Flavivirus/efeitos dos fármacos , Flavivirus/enzimologia , Flavivirus/genética , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Hepacivirus/genética , Humanos , Pirazinas/química , Pirazinas/farmacologia , Infecções por Vírus de RNA/epidemiologia , Vírus de RNA/efeitos dos fármacos , /metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
15.
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
17.
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
18.
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
19.
Front Immunol ; 11: 592370, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33250897

RESUMO

Prior to 2020, the threat of a novel viral pandemic was omnipresent but largely ignored. Just 12 months prior to the Coronavirus disease 2019 (COVID-19) pandemic our team received funding from the Coalition for Epidemic Preparedness Innovations (CEPI) to establish and validate a rapid response pipeline for subunit vaccine development based on our proprietary Molecular Clamp platform. Throughout the course of 2019 we conducted two mock tests of our system for rapid antigen production against two potential, emerging viral pathogens, Achimota paramyxovirus and Wenzhou mammarenavirus. For each virus we expressed a small panel of recombinant variants of the membrane fusion protein and screened for expression level, product homogeneity, and the presence of the expected trimeric pre-fusion conformation. Lessons learned from this exercise paved the way for our response to COVID-19, for which our candidate antigen is currently in phase I clinical trial.


Assuntos
Desenho de Fármacos , Vacinas de Subunidades , Animais , Arenaviridae , Defesa Civil , Ensaios Clínicos como Assunto , Humanos , Estrutura Molecular , Paramyxovirinae/imunologia , Fatores de Tempo , Vacinas de Subunidades/química , Vacinas Virais
20.
Nat Commun ; 11(1): 5981, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239628

RESUMO

Targeting a specific chemokine/receptor axis in atherosclerosis remains challenging. Soluble receptor-based strategies are not established for chemokine receptors due to their discontinuous architecture. Macrophage migration-inhibitory factor (MIF) is an atypical chemokine that promotes atherosclerosis through CXC-motif chemokine receptor-4 (CXCR4). However, CXCR4/CXCL12 interactions also mediate atheroprotection. Here, we show that constrained 31-residue-peptides ('msR4Ms') designed to mimic the CXCR4-binding site to MIF, selectively bind MIF with nanomolar affinity and block MIF/CXCR4 without affecting CXCL12/CXCR4. We identify msR4M-L1, which blocks MIF- but not CXCL12-elicited CXCR4 vascular cell activities. Its potency compares well with established MIF inhibitors, whereas msR4M-L1 does not interfere with cardioprotective MIF/CD74 signaling. In vivo-administered msR4M-L1 enriches in atherosclerotic plaques, blocks arterial leukocyte adhesion, and inhibits atherosclerosis and inflammation in hyperlipidemic Apoe-/- mice in vivo. Finally, msR4M-L1 binds to MIF in plaques from human carotid-endarterectomy specimens. Together, we establish an engineered GPCR-ectodomain-based mimicry principle that differentiates between disease-exacerbating and -protective pathways and chemokine-selectively interferes with atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Oxirredutases Intramoleculares/antagonistas & inibidores , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Fragmentos de Peptídeos/farmacologia , Receptores CXCR4/metabolismo , Idoso , Animais , Antígenos CD/metabolismo , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/cirurgia , Sítios de Ligação , Artéria Carótida Primitiva/patologia , Artéria Carótida Primitiva/cirurgia , Quimiocina CXCL12/metabolismo , Cristalografia por Raios X , Modelos Animais de Doenças , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Endarterectomia das Carótidas , Feminino , Humanos , Oxirredutases Intramoleculares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Fragmentos de Peptídeos/uso terapêutico , Receptores CXCR4/química , Receptores CXCR4/ultraestrutura , Sialiltransferases/metabolismo , Transdução de Sinais/efeitos dos fármacos
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