Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 63
Filtrar
1.
Journal of Computational Biophysics & Chemistry ; : 1-14, 2022.
Artigo em Inglês | Academic Search Complete | ID: covidwho-1832572

RESUMO

According to the limited medications for COVID-19, natural products gained increasing attention. Scientific indications revealed the effect of biflavonoids (BFs) against respiratory syndrome viruses. The functional importance of 3-chymotrypsin-like protease (3CLpro) in forming viral RNA raises its potential to be targeted in SARS-CoV2. This study is devoted to the computational analysis of privileged BFs within the SARS-CoV2 3CLpro active site. Docking and molecular dynamics (MD) simulations were collectively used to explore the most probable binding modes and stable ligand–enzyme chemical interactions. Despite the structural resemblance, a wide range of binding affinities was retrieved for BFs (ΔGb−7.11−12.66kcal/mol). Garciniaflavone C (ΔGb−12.66kcal/mol), 7,7′′, 4′′′-tri-O-methylagathisflavone (ΔGb−12.16kcal/mol) and 8,8′′-biapigenil (ΔGb−12.08kcal/mol) were top enzyme binders. The stability of acquired complexes was analyzed through 50-ns all-atom MD simulations. Garciniaflavone C, 7,7′′, 4′′′-tri-O-methylagathisflavone and 8,8′′-biapigenil showed 29%, 22% and 23% persevered binding residues, respectively. SARS-CoV2-garciniaflavone C complex was mediated by several nonpolar interactions. MD simulations assigned H-bond interaction between the catalytic dyad residue Cys145 and garciniaflavone C. 7,7′′, 4′′′-tri-O-methylagathisflavone participated in a π-cation interaction to His41. Solvent accessible surface area distribution indicated the sufficiency of MD simulation time (50ns) to screen equilibrated complex systems. Although a detailed pharmacological mechanism is to be elucidated, our findings indicated superior binding stability of 7,7′′, 4′′′-tri-O-methylagathisflavone within SARS-CoV2 active site. While the biological function of the majority of BF derivatives remains to be elucidated, results of the current study revealed key structural features and potentials of privileged BFs for further structure-guided optimization toward potent SARS-CoV2 3CLpro inhibitors. [ FROM AUTHOR] Copyright of Journal of Computational Biophysics & Chemistry is the property of World Scientific Publishing Company and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

2.
Applied Organometallic Chemistry ; 2022.
Artigo em Inglês | Scopus | ID: covidwho-1787645

RESUMO

Novel transition metal-based complexes that may be of value as biological agents and/or nonlinear optical materials, Zn (II) and Cu (II) transition metal complexes of 6-chloropyridine-2-carboxylic acid (LH), were successfully synthesized. The chemical structure of each complex was characterized using X-ray diffraction (XRD) method and FT-IR spectroscopy. XRD and FT-IR demonstrated that L ligand coordinate to central metal ions through the donor N and O atoms. By coordinating two H2O ligand to Zn (II) ion, a distorted octahedral complex geometry was constructed for 1. As for 2, a distorted trigonal bipyramidal coordination geometry was obtained by a H2O ligand coordination to Cu (II) ion. Theoretical studies using B3LYP/6-311++G(d,p)-LanL2DZ were performed to further validate the proposed structures. The molecular docking of 1 to SARS-CoV-2 main protease (PDB: 6LU7) gives a binding energy of −5.24 kcal/mol and inhibition constant of 144.6 μM, demonstrating that 1 is a more promising candidate to biologically active complexes than 2. The first-order hyperpolarizability (β) parameter for 1 and 2 was calculated as 0.88 × 10−30 and 10.40 × 10−30 esu, respectively. These β values also demonstrated that 2 exhibits more effective NLO character than 1 due to the electronic configuration and coordination geometry. © 2022 John Wiley & Sons, Ltd.

3.
15th International Conference on Pattern Recognition and Information Processing, PRIP 2021 ; 1562 CCIS:120-136, 2022.
Artigo em Inglês | Scopus | ID: covidwho-1777668

RESUMO

Two generative autoencoder models for designing novel drug-like compounds able to block the catalytic site of the SARS-CoV-2 main protease (MPro) critical for mediating viral replication and transcription were developed using deep learning methods. To do this, the following steps were performed: (i) architectures of two neural networks were constructed;(ii) a virtual compound library of potential anti-SARS-CoV-2 MPro agents for training two neural networks was formed;(iii) molecular docking of all compounds from this library with MPro was made and calculations of the values of binding free energy were carried out;(iv) two neural networks were trained followed by estimation of the learning outcomes and work of two autoencoders involving several generation modes. Validation of autoencoders and their comparison revealed the best combination of the neural network architecture with the generation mode, which allows one to generate good chemical scaffold for the design of novel antiviral drugs with suitable pharmaceutical properties. © 2022, Springer Nature Switzerland AG.

4.
Chem Zvesti ; : 1-12, 2022 Apr 03.
Artigo em Inglês | MEDLINE | ID: covidwho-1777799

RESUMO

The COVID-19 pandemic emerged in 2019, bringing with it the need for greater stores of effective antiviral drugs. This paper deals with the conformation-independent, QSAR model, developed by employing the Monte Carlo optimization method, as well as molecular graphs and the SMILES notation-based descriptors for the purpose of modeling the SARS-CoV-3CLpro enzyme inhibition. The main purpose was developing a reproducible model involving easy interpretation, utilized for a quick prediction of the inhibitory activity of SAR-CoV-3CLpro. The following statistical parameters were present in the best-developed QSAR model: (training set) R 2 = 0.9314, Q 2 = 0.9271; (test set) R 2 = 0.9243, Q 2 = 0.8986. Molecular fragments, defined as SMILES notation descriptors, that have a positive and negative impact on 3CLpro inhibition were identified on the basis of the results obtained for structural indicators, and were applied to the computer-aided design of five new compounds with (4-methoxyphenyl)[2-(methylsulfanyl)-6,7-dihydro-1H-[1,4]dioxino[2,3-f]benzimidazol-1-yl]methanone as a template molecule. Molecular docking studies were used to examine the potential inhibition effect of designed molecules on SARS-CoV-3CLpro enzyme inhibition and obtained results have high correlation with the QSAR modeling results. In addition, the interactions between the designed molecules and amino acids from the 3CLpro active site were determined, and the energies they yield were calculated. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-022-02170-8.

5.
Molecules ; 27(6)2022 Mar 11.
Artigo em Inglês | MEDLINE | ID: covidwho-1765795

RESUMO

Protein-protein assemblies act as a key component in numerous cellular processes. Their accurate modeling at the atomic level remains a challenge for structural biology. To address this challenge, several docking and a handful of deep learning methodologies focus on modeling protein-protein interfaces. Although the outcome of these methods has been assessed using static reference structures, more and more data point to the fact that the interaction stability and specificity is encoded in the dynamics of these interfaces. Therefore, this dynamics information must be taken into account when modeling and assessing protein interactions at the atomistic scale. Expanding on this, our review initially focuses on the recent computational strategies aiming at investigating protein-protein interfaces in a dynamic fashion using enhanced sampling, multi-scale modeling, and experimental data integration. Then, we discuss how interface dynamics report on the function of protein assemblies in globular complexes, in fuzzy complexes containing intrinsically disordered proteins, as well as in active complexes, where chemical reactions take place across the protein-protein interface.


Assuntos
Proteínas Intrinsicamente Desordenadas , Proteínas Intrinsicamente Desordenadas/química
6.
Chemometr Intell Lab Syst ; 224: 104535, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: covidwho-1739603

RESUMO

COVID-19 disease causes serious respiratory illnesses. Therefore, accurate identification of the viral infection cycle plays a key role in designing appropriate vaccines. The risk of this disease depends on proteins that interact with human receptors. In this paper, we formulate a novel model for COVID-19 named "amino acid encoding based prediction" (AAPred). This model is accurate, classifies the various coronavirus types, and distinguishes SARS-CoV-2 from other coronaviruses. With the AAPred model, we reduce the number of features to enhance its performance by selecting the most important ones employing statistical criteria. The protein sequence of SARS-CoV-2 for understanding the viral infection cycle is analyzed. Six machine learning classifiers related to decision trees, k-nearest neighbors, random forest, support vector machine, bagging ensemble, and gradient boosting are used to evaluate the model in terms of accuracy, precision, sensitivity, and specificity. We implement the obtained results computationally and apply them to real data from the National Genomics Data Center. The experimental results report that the AAPred model reduces the features to seven of them. The average accuracy of the 10-fold cross-validation is 98.69%, precision is 98.72%, sensitivity is 96.81%, and specificity is 97.72%. The features are selected utilizing information gain and classified with random forest. The proposed model predicts the type of Coronavirus and reduces the number of extracted features. We identify that SARS-CoV-2 has similar physicochemical characteristics in some regions of SARS-CoV. Also, we report that SARS-CoV-2 has similar infection cycles and sequences in some regions of SARS CoV indicating the affectedness of vaccines on SARS-CoV-2. A comparison with deep learning shows similar results with our method.

7.
Molecules ; 27(6)2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: covidwho-1732133

RESUMO

The wild-type SARS-CoV-2 has continuously evolved into several variants with increased transmissibility and virulence. The Delta variant which was initially identified in India created a devastating impact throughout the country during the second wave. While the efficacy of the existing vaccines against the latest SARS-CoV-2 variants remains unclear, extensive research is being carried out to develop potential antiviral drugs through approaches like in silico screening and drug-repurposing. This study aimed to conduct the docking-based virtual screening of 50 potential phytochemical compounds against a Spike glycoprotein of the wild-type and the Delta SARS-CoV-2 variant. Subsequently, molecular docking was performed for the five best compounds, such as Lupeol, Betulin, Hypericin, Corilagin, and Geraniin, along with synthetic controls. From the results obtained, it was evident that Lupeol exhibited a remarkable binding affinity towards the wild-type Spike protein (-8.54 kcal/mol), while Betulin showed significant binding interactions with the mutated Spike protein (-8.83 kcal/mol), respectively. The binding energy values of the selected plant compounds were slightly higher than that of the controls. Key hydrogen bonding and hydrophobic interactions of the resulting complexes were visualized, which explained their greater binding affinity against the target proteins-the Delta S protein of SARS-CoV-2, in particular. The lower RMSD, the RMSF values of the complexes and the ligands, Rg, H-bonds, and the binding free energies of the complexes together revealed the stability of the complexes and significant binding affinities of the ligands towards the target proteins. Our study suggests that Lupeol and Betulin could be considered as potential ligands for SARS-CoV-2 spike antagonists. Further experimental validations might provide new insights for the possible antiviral therapeutic interventions of the identified lead compounds and their analogs against COVID-19 infection.


Assuntos
Antivirais , COVID-19 , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética
8.
Journal of Molecular Structure ; 1258, 2022.
Artigo em Inglês | Scopus | ID: covidwho-1730002

RESUMO

Cepharanthine, a natural alkaloid obtained from the Stephania cepharantha Hayata plant, that has antitumor, anti-inflammatory, antioxidative, antiparasitic, and antiviral properties, has been widely used for many years to treat a wide variety of diseases in Japan. However, to elucidate its mechanism of action needs further study. This study aimed to enlighten the molecular structure, and the anticancer and antiviral action mechanisms of Cepharanthine. To evaluate the molecular structure of Cepharanthine, conformational analysis was performed using the DFT/B3LYP with 6-31G(d,p) basis set. The obtained most stable molecular geometry was then optimized at the DFT/B3LYP/6-311++G(d,p) level of theory. The observed IR and Raman bands were compared with harmonic vibrational frequencies of the optimized structure of cepharanthine, calculated using the same level of theory, and assigned on the base of potential energy distribution (PED). The experimental UV-Vis absorption spectrum was recorded and compared with the simulated Time Dependent (TD-DFT/B3LYP/6-311++G(d,p)) method. Moreover, 1H and 13C NMR spectra has been calculated and compared by the experimental spectra. To reveal pharmacological importance of Cepharanthine, a molecular docking study was performed with NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) receptor which controls transcription of DNA, cytokine production and cell survival. Molecular docking simulations revealed that Cepharanthine showed strong binding affinity to NF-κB receptor (ΔG = - 8.9 kcal/mol). In addition, to enlight the antiviral properties of cepharantine and to explore the possibility of its use in the treatment of COVID-19, the interactions of cepharanthine with ACE2, apo and holo forms of COVID-19 main protease enzyme (Mpro) and spike glycoprotein of SARSCoV-2 receptors were investigated. © 2022 Elsevier B.V.

9.
Chem Pharm Bull (Tokyo) ; 70(3): 195-198, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: covidwho-1714683

RESUMO

We investigated similar compounds to ebselen and tideglusib, which exhibit strong activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), using Molecular ACCess System (MACCS) keys. Four candidate compounds were identified. One of them, phenyl-benzothiazol-3-one, showed coronavirus-specific 3C-like (3CL) protease inhibitory activity. The results indicated that a similarity score above 0.81 is a good indicator of activity for ebselen-and-tideglusib-like compounds. Subsequently, we simulated the ring-cleavage Michael reaction of ebselen at the Se center, which is responsible for its 3CL protease inhibitory activity, and determined the activation free energy of the reaction. The results showed that reaction simulation is a useful tool for estimating the activity of inhibitory compounds that undergo Michael addition reactions with the relevant cysteine S atom of 3CL proteases.


Assuntos
COVID-19 , Inibidores de Proteases , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Humanos , Inibidores de Proteases/farmacologia , SARS-CoV-2
10.
3rd IEEE/ACM International Workshop on HPC for Urgent Decision Making, UrgentHPC 2021 ; : 1-10, 2021.
Artigo em Inglês | Scopus | ID: covidwho-1705928

RESUMO

Over the past 18 months, the need to perform atomic detail molecular dynamics simulations of the SARS-CoV-2 virion, its spike protein, and other structures related to the viral infection cycle has led biomedical researchers worldwide to urgently seek out all available biomolecular structure information, appropriate molecular modeling and simulation software, and the necessary computing resources to conduct their work. We describe our experiences from several COVID-19 research collaborations and the challenges they presented in terms of our molecular modeling software development and support efforts, our laboratory's local computing environment, and our scientists' use of non-traditional HPC hardware platforms such as public clouds for large scale parallel molecular dynamics simulations. © 2021 IEEE.

11.
PeerJ ; 10: e12929, 2022.
Artigo em Inglês | MEDLINE | ID: covidwho-1687415

RESUMO

The spread of SARS-CoV-2, the causative agent for COVID-19, has led to a global and deadly pandemic. To date, few drugs have been approved for treating SARS-CoV-2 infections. In this study, a structure-based approach was adopted using the SARS-CoV-2 main protease (Mpro) and a carefully selected dataset of 37,060 compounds comprising Mpro and antiviral protein-specific libraries. The compounds passed two-step docking filtration, starting with standard precision (SP) followed by extra precision (XP) runs. Fourteen compounds with the highest XP docking scores were examined by 20 ns molecular dynamics simulations (MDs). Based on backbone route mean square deviations (RMSD) and molecular mechanics/generalized Born surface area (MM/GBSA) binding energy, four drugs were selected for comprehensive MDs analysis at 100 ns. Results indicated that birinapant, atazanavir, and ritonavir potently bound and stabilized SARS-CoV-2 Mpro structure. Binding energies higher than -102 kcal/mol, RMSD values <0.22 nm, formation of several hydrogen bonds with Mpro, favourable electrostatic contributions, and low radii of gyration were among the estimated factors contributing to the strength of the binding of these three compounds with Mpro. The top two compounds, atazanavir and birinapant, were tested for their ability to prevent SARS-CoV-2 plaque formation. At 10 µM of birinapant concentration, antiviral tests against SARS-CoV-2 demonstrated a 37% reduction of virus multiplication. Antiviral assays demonstrated that birinapant has high anti-SARS-CoV-2 activity in the low micromolar range, with an IC50 value of 18 ± 3.6 µM. Therefore, birinapant is a candidate for further investigation to determine whether it is a feasible therapy option.

12.
Bioorg Chem ; 119: 105574, 2022 02.
Artigo em Inglês | MEDLINE | ID: covidwho-1654103

RESUMO

The COVID-19 pandemic caused by the SARS-CoV-2 virus has led to a major public health burden and has resulted in millions of deaths worldwide. As effective treatments are limited, there is a significant requirement for high-throughput, low resource methods for the discovery of novel antivirals. The SARS-CoV-2 spike protein plays a key role in viral entry and has been identified as a therapeutic target. Using the available spike crystal structure, we performed a virtual screen with a library of 527 209 natural compounds against the receptor binding domain of this protein. Top hits from this screen were subjected to a second, more comprehensive molecular docking experiment and filtered for favourable ADMET properties. The in vitro activity of 10 highly ranked compounds was assessed using a virus neutralisation assay designed to facilitate viral entry in a physiologically relevant manner via the plasma membrane route. Subsequently, four compounds ZINC02111387, ZINC02122196, SN00074072 and ZINC04090608 were identified to possess antiviral activity in the µM range. These findings validate the virtual screening method as a tool for identifying novel antivirals and provide a basis for future drug development against SARS-CoV-2.


Assuntos
Produtos Biológicos/farmacologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Animais , Antivirais/farmacologia , Produtos Biológicos/toxicidade , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Testes de Neutralização , Reprodutibilidade dos Testes , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
13.
Cureus ; 14(1): e20980, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: covidwho-1630479

RESUMO

Chlorpheniramine maleate, a widely used over-the-counter antihistamine, has been identified as a structural analog of aminoquinolines known to possess antiviral activity against the Betacoronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). Structural similarities include the chlorophenyl group, pyridine ring, alkyl sidechain, and terminal tertiary amine; the comparison of aqueous energy-minimized structures indicates significant three-dimensional similarity as well. Preliminary clinical evidence supports these conclusions. The present study suggests that chlorpheniramine possesses antiviral activity against COVID-19.

14.
Russ Chem Bull ; 70(11): 2084-2089, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1626439

RESUMO

Molecular modeling tools were applied to design a potential covalent inhibitor of the main protease (Mpro) of the SARS-CoV-2 virus and to investigate its interaction with the enzyme. The compound includes a benzoisothiazolone (BZT) moiety of antimalarial drugs and a 5-fluoro-6-nitropyrimidine-2,4(1.H,3H)-dione (FNP) moiety mimicking motifs of inhibitors of other cysteine proteases. The BZT moiety provides a fair binding of the ligand on the protein surface, whereas the warhead FNP is responsible for efficient nucleophilic aromatic substitution reaction with the catalytic cysteine residue in the Mpro active site, leading to a stable covalent adduct. According to supercomputer calculations of the reaction energy profile using the quantum mechanics/molecular mechanics method, the energy of the covalent adduct is 21 kcal mol-1 below the energy of the reactants, while the highest barrier along the reaction pathway is 9 kcal mol-1. These estimates indicate that the reaction can proceed efficiently and can block the Mpro enzyme. The computed structures along the reaction path illustrate the nucleophilic aromatic substitution (SNAr) mechanism in enzymes. The results of this study are important for the choice of potential drugs blocking the development of coronavirus infection.

15.
Chemistryselect ; 6(47):13616-13626, 2021.
Artigo em Inglês | Web of Science | ID: covidwho-1588879

RESUMO

Major protease enzyme of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 M-pro) is one of the key enzymes of viral replication which amuses many scientists as a promising drug target. Nonetheless, few studies reported new synthetic small molecule inhibitors of the M-pro but many were repurposing drugs such as chloroquine or predicting the activity based on in silico results. This study had the privilege of synthesizing new coumarin-based derivatives with possible M-pro inhibition based on the previously reported ligand-based pharmacophore model. Compound 3 showed comparable M-pro inhibitory activity to chloroquine with IC50 15.0 and 13.1 mu g/mL, respectively. Moreover, compounds 4 b, 4 d, 5 b, 5 c, 5 e and 5 g managed to inhibit the M-pro enzymatic activity by more than 50.0 % at 100 mu M among which 5 g showed 63.9 % inhibition and IC50 25.8 mu g/mL. The binding conformations of the promising compounds were illustrated using molecular docking as well as their drug-likeness and ADMET properties. A pharmacophore model was generated using the compounds with more than 50.0 % M-pro inhibition to annotate the essential moieties for enzyme binding. All compounds were fully characterized using the conventional spectroscopic and microanalyses methods.

16.
Drug Discov Today ; 2021 Dec 23.
Artigo em Inglês | MEDLINE | ID: covidwho-1587949

RESUMO

The rapidly evolving Coronavirus 2019 (COVID-19) pandemic has led to millions of deaths around the world, highlighting the pressing need to develop effective antiviral pharmaceuticals. Recent efforts with computer-aided rational drug discovery have allowed detailed examination of drug-macromolecule interactions primarily by molecular mechanics (MM) techniques. Less widely applied in COVID-19 drug modeling is density functional theory (DFT), a quantum mechanics (QM) method that enables electronic structure calculations and elucidations of reaction mechanisms. Here, we review recent advances in applying DFT in molecular modeling studies of COVID-19 pharmaceuticals. We start by providing an overview of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs and targets, followed by a brief introduction to DFT. We then provide a discussion of different approaches by which DFT has been applied. Finally, we discuss essential factors to consider when incorporating DFT in future drug modeling research.

17.
Comput Biol Chem ; 96: 107613, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: covidwho-1549716

RESUMO

Coronavirus Disease 2019 (COVID-19) is an ongoing global health emergency that has caused tremendous stress and loss of life worldwide. The viral spike glycoprotein is a critical molecule mediating transmission of SARS-CoV-2 by interacting with human ACE2. However, through the course of the pandemics, there has not been a thorough analysis of the spike protein mutations, and on how these mutants influence the transmission of SARS-CoV-2. Besides, cases of SARS-CoV-2 infection among pets and wild animals have been reported, so the susceptibility of these animals requires great attention to investigate, as they may also link to the renewed question of a possible intermediate host for SARS-CoV-2 before it was transmitted to humans. With over 226,000 SARS-CoV-2 sequences obtained, we found 1573 missense mutations in the spike gene, and 226 of them were within the receptor-binding domain (RBD) region that directly interacts with human ACE2. Modeling the interactions between SARS-CoV-2 spike mutants and ACE2 molecules showed that most of the 74 missense mutations in the RBD region of the interaction interface had little impact on spike binding to ACE2, whereas several within the spike RBD increased the binding affinity toward human ACE2 thus making the virus likely more contagious. On the other hand, modeling the interactions between animal ACE2 molecules and SARS-CoV-2 spike revealed that many pets and wild animals' ACE2 had a variable binding ability. Particularly, ACE2 of bamboo rat had stronger binding to SARS-CoV-2 spike protein, whereas that of mole, vole, Mus pahari, palm civet, and pangolin had a weaker binding compared to human ACE2. Our results provide structural insights into the impact on interactions of the SARS-CoV-2 spike mutants to human ACE2, and shed light on SARS-CoV-2 transmission in pets and wild animals, and possible clues to the intermediate host(s) for SARS-CoV-2.


Assuntos
Enzima de Conversão de Angiotensina 2/química , COVID-19/veterinária , COVID-19/virologia , Mutação de Sentido Incorreto , SARS-CoV-2/química , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Enzima de Conversão de Angiotensina 2/genética , Animais , Animais Selvagens/genética , Animais Selvagens/virologia , COVID-19/transmissão , Biologia Computacional , Interações entre Hospedeiro e Microrganismos/genética , Especificidade de Hospedeiro/genética , Humanos , Simulação de Dinâmica Molecular , Pandemias/veterinária , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/genética , Animais de Estimação/genética , Animais de Estimação/virologia , Domínios e Motivos de Interação entre Proteínas/genética , Fatores de Risco
18.
EXCLI J ; 20: 1517-1525, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1513278

RESUMO

Acute respiratory distress syndrome (ARDS) is the main danger to the life of patients with pneumonia caused by SARS-CoV-2. At the same time, respiratory failure (RF) after ARDS can persist for a long time despite intensive therapy. Therefore, it is important to develop new effective approaches for restoring the ventilation function of the lungs after COVID-19. Here, we present a case report of effective application of short-term inhalations of xenon-oxygen (Xe/O2) gas mixture for treatment of RF and neuropsychiatric disorders (NPD) associated with COVID-19. The patient inhaled a gas mixture of 70 % Xe and 30 % O2. We used multispiral computed tomography, evaluated psychometry, studied hematological and biochemical blood parameters, and applied some other methods of clinical studies to assess the therapeutic effectiveness of Xe inhalation. Also, we studied the mechanism of action of xenon with computer modeling. The clinical case showed the high efficacy of Xe/O2 mixture for treating severe RF and NPD after SARS-CoV-2 infection. Xenon inhalations dramatically increased oxygen saturation and the degree of pneumatization of the lungs. We found out that in coronavirus pneumonia, saturated phospholipids of surfactant are transferred to the solid-ordered phase, which disrupts the surface tension of the alveoli and alveolar gas exchange. Using molecular modeling methods, we demonstrated that the xenon atom increases the distance between the acyl chains of phospholipids due to the van der Waals dispersion interaction. These changes allow for the phase transition of phospholipids from the solid-ordered phase to the liquid phase and restore the functional activity of the surfactant. The findings suggest the feasibility of conducting studies on the effectiveness of Xe/O2 inhalations for treating ARDS in SARS-CoV-2 infection.

19.
Front Chem ; 9: 722633, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1497023

RESUMO

Although SARS-CoV-2 entry to cells strictly depends on angiotensin-converting enzyme 2 (ACE2), the virus also needs transmembrane serine protease 2 (TMPRSS2) for its spike protein priming. It has been shown that the entrance of SARS-CoV-2 through ACE2 can be blocked by cellular TMPRSS2 blockers. The main aim of this study was to find potential inhibitor(s) of TMPRSS2 through virtual screening against a homology model of TMPRSS2 using the library of marine natural products (MNPs). The homology modeling technique for generating a three-dimensional structure of TMPRSS2 was applied. Molecular docking, MM-GBSA and absorption, distribution, metabolism, excretion (ADME) evaluations were performed to investigate the inhibitory activity of marine natural products (MNPs) against TMPRSS2 and their pharmacokinetic properties. Camostat and nafamostat mesylate were used as the standard inhibitory molecules. Seven MNPs were able to inhibit TMPRSS2 better than the standard compounds. MNP 10 with CAS number 107503-09-3, called Watasenia ß-D- Preluciferyl glucopyrasoiuronic acid, was found to be the best inhibitor of TMPRSS2 with acceptable pharmacokinetic properties. Herein, for the first time, a new marine natural product was introduced with potent inhibitory effects against TMPRSS2. MNP 10 exhibited favorable drug-like pharmacokinetic properties and it promises a novel TMPRSS2 blocker to combat SARS-CoV-2.

20.
Synlett ; 33(5): 458-463, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: covidwho-1472233

RESUMO

The COVID-19 pandemic prompted many scientists to investigate remedies against SARS-CoV-2 and related viruses that are likely to appear in the future. As the main protease of the virus, MPro, is highly conserved among coronaviruses, it has emerged as a prime target for developing inhibitors. Using a combination of virtual screening and molecular modeling, we identified small molecules that were easily accessible and could be quickly diversified. Biochemical assays confirmed a class of pyridones as low micromolar non-covalent inhibitors of the viral main protease.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA