Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 37.709
Filtrar
1.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502335

RESUMO

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


Assuntos
Antivirais/farmacologia , Simulação de Acoplamento Molecular , Oligopeptídeos/química , Peptídeos/metabolismo , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Antivirais/metabolismo , Antivirais/uso terapêutico , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/virologia , Domínio Catalítico , Linhagem Celular , Citomegalovirus/efeitos dos fármacos , Reposicionamento de Medicamentos , Herpesvirus Humano 3/efeitos dos fármacos , Humanos , Simulação de Dinâmica Molecular , Peptídeos/síntese química , Peptídeos/farmacologia , Peptídeos/uso terapêutico , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/metabolismo
2.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502340

RESUMO

The SARS-CoV-2 main protease (Mpro) is one of the molecular targets for drug design. Effective vaccines have been identified as a long-term solution but the rate at which they are being administered is slow in several countries, and mutations of SARS-CoV-2 could render them less effective. Moreover, remdesivir seems to work only with some types of COVID-19 patients. Hence, the continuous investigation of new treatments for this disease is pivotal. This study investigated the inhibitory role of natural products against SARS-CoV-2 Mpro as repurposable agents in the treatment of coronavirus disease 2019 (COVID-19). Through in silico approach, selected flavonoids were docked into the active site of Mpro. The free energies of the ligands complexed with Mpro were computationally estimated using the molecular mechanics-generalized Born surface area (MM/GBSA) method. In addition, the inhibition process of SARS-CoV-2 Mpro with these ligands was simulated at 100 ns in order to uncover the dynamic behavior and complex stability. The docking results showed that the selected flavonoids exhibited good poses in the binding domain of Mpro. The amino acid residues involved in the binding of the selected ligands correlated well with the residues involved with the mechanism-based inhibitor (N3) and the docking score of Quercetin-3-O-Neohesperidoside (-16.8 Kcal/mol) ranked efficiently with this inhibitor (-16.5 Kcal/mol). In addition, single-structure MM/GBSA rescoring method showed that Quercetin-3-O-Neohesperidoside (-87.60 Kcal/mol) is more energetically favored than N3 (-80.88 Kcal/mol) and other ligands (Myricetin 3-Rutinoside (-87.50 Kcal/mol), Quercetin 3-Rhamnoside (-80.17 Kcal/mol), Rutin (-58.98 Kcal/mol), and Myricitrin (-49.22 Kcal/mol). The molecular dynamics simulation (MDs) pinpointed the stability of these complexes over the course of 100 ns with reduced RMSD and RMSF. Based on the docking results and energy calculation, together with the RMSD of 1.98 ± 0.19 Å and RMSF of 1.00 ± 0.51 Å, Quercetin-3-O-Neohesperidoside is a better inhibitor of Mpro compared to N3 and other selected ligands and can be repurposed as a drug candidate for the treatment of COVID-19. In addition, this study demonstrated that in silico docking, free energy calculations, and MDs, respectively, are applicable to estimating the interaction, energetics, and dynamic behavior of molecular targets by natural products and can be used to direct the development of novel target function modulators.


Assuntos
Produtos Biológicos/metabolismo , SARS-CoV-2/enzimologia , Proteínas da Matriz Viral/metabolismo , Sítios de Ligação , Produtos Biológicos/química , Produtos Biológicos/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/patologia , COVID-19/virologia , Domínio Catalítico , Desenho de Fármacos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Inibidores de Proteases/uso terapêutico , Quercetina/análogos & derivados , Quercetina/química , Quercetina/metabolismo , Quercetina/uso terapêutico , SARS-CoV-2/isolamento & purificação , Proteínas da Matriz Viral/química
3.
Nat Commun ; 12(1): 5236, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475399

RESUMO

New drugs are urgently needed to combat the global TB epidemic. Targeting simultaneously multiple respiratory enzyme complexes of Mycobacterium tuberculosis is regarded as one of the most effective treatment options to shorten drug administration regimes, and reduce the opportunity for the emergence of drug resistance. During infection and proliferation, the cytochrome bd oxidase plays a crucial role for mycobacterial pathophysiology by maintaining aerobic respiration at limited oxygen concentrations. Here, we present the cryo-EM structure of the cytochrome bd oxidase from M. tuberculosis at 2.5 Å. In conjunction with atomistic molecular dynamics (MD) simulation studies we discovered a previously unknown MK-9-binding site, as well as a unique disulfide bond within the Q-loop domain that defines an inactive conformation of the canonical quinol oxidation site in Actinobacteria. Our detailed insights into the long-sought atomic framework of the cytochrome bd oxidase from M. tuberculosis will form the basis for the design of highly specific drugs to act on this enzyme.


Assuntos
Grupo dos Citocromos b/química , Grupo dos Citocromos d/química , Complexo de Proteínas da Cadeia de Transporte de Elétrons/química , Mycobacterium tuberculosis/enzimologia , Proteínas de Bactérias/química , Sítios de Ligação , Microscopia Crioeletrônica , Simulação de Dinâmica Molecular , Oxirredutases/química , Conformação Proteica , Subunidades Proteicas , Vitamina K 2/análogos & derivados , Vitamina K 2/química
4.
J Mol Model ; 27(10): 276, 2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34480634

RESUMO

Rimegepant is a new medicine developed for the management of chronic headache due to migraine. This manuscript is an attempt to study the various structural, physical, and chemical properties of the molecules. The molecule was optimized using B3LYP functional with 6-311G + (2d,p) basis set. Excited state properties of the compound were studied using CAM-B3LYP functional with same basis sets using IEFPCM model in methanol for the implicit solvent atmosphere. The various electronic descriptors helped to identify the reactivity behavior and stability. The compound is found to possess good nonlinear optical properties in the gas phase. The various intramolecular electronic delocalizations and non-covalent interactions were analyzed and explained. As the compound contain several heterocyclic nitrogen atoms, they have potential proton abstraction features, which was analyzed energetically. The most important result from this study is from the molecular docking analysis which indicates that rimegepant binds irreversibly with three established SARS-CoV-2 proteins with ID 6LU7, 6M03, and 6W63 with docking scores - 9.2988, - 8.3629, and - 9.5421 kcal/mol respectively. Further assessment of docked complexes with molecular dynamics simulations revealed that hydrophobic interactions, water bridges, and π-π interactions play a significant role in stabilizing the ligand within the binding region of respective proteins. MMGBSA-free energies further demonstrated that rimegepant is more stable when complexed with 6LU7 among the selected PDB models. As the pharmacology and pharmacokinetics of this molecule are already established, rimegepant can be considered as an ideal candidate with potential for use in the treatment of COVID patients after clinical studies.


Assuntos
Simulação de Dinâmica Molecular , Piperidinas/química , Prótons , Piridinas/química , SARS-CoV-2/química , Proteínas Virais/química , SARS-CoV-2/metabolismo , Proteínas Virais/metabolismo
5.
Molecules ; 26(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34500548

RESUMO

The emergence of COVID-19 continues to pose severe threats to global public health. The pandemic has infected over 171 million people and claimed more than 3.5 million lives to date. We investigated the binding potential of antiviral cyanobacterial proteins including cyanovirin-N, scytovirin and phycocyanin with fundamental proteins involved in attachment and replication of SARS-CoV-2. Cyanovirin-N displayed the highest binding energy scores (-16.8 ± 0.02 kcal/mol, -12.3 ± 0.03 kcal/mol and -13.4 ± 0.02 kcal/mol, respectively) with the spike protein, the main protease (Mpro) and the papainlike protease (PLpro) of SARS-CoV-2. Cyanovirin-N was observed to interact with the crucial residues involved in the attachment of the human ACE2 receptor. Analysis of the binding affinities calculated employing the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) approach revealed that all forms of energy, except the polar solvation energy, favourably contributed to the interactions of cyanovirin-N with the viral proteins. With particular emphasis on cyanovirin-N, the current work presents evidence for the potential inhibition of SARS-CoV-2 by cyanobacterial proteins, and offers the opportunity for in vitro and in vivo experiments to deploy the cyanobacterial proteins as valuable therapeutics against COVID-19.


Assuntos
Antivirais/farmacologia , Proteínas de Bactérias/farmacologia , COVID-19/tratamento farmacológico , Inibidores de Protease de Coronavírus/farmacologia , Antivirais/uso terapêutico , Proteínas de Bactérias/uso terapêutico , Proteínas de Bactérias/ultraestrutura , COVID-19/virologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Proteases 3C de Coronavírus/ultraestrutura , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Proteases Semelhantes à Papaína de Coronavírus/ultraestrutura , Inibidores de Protease de Coronavírus/uso terapêutico , Inibidores de Protease de Coronavírus/ultraestrutura , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Mapeamento de Interação de Proteínas , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/ultraestrutura , Difração de Raios X
6.
Molecules ; 26(17)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34500664

RESUMO

This study aims to identify and isolate the secondary metabolites of Zingiber officinale using GC-MS, preparative TLC, and LC-MS/MS methods, to evaluate the inhibitory potency on SARS-CoV-2 3 chymotrypsin-like protease enzyme, as well as to study the molecular interaction and stability by using docking and molecular dynamics simulations. GC-MS analysis suggested for the isolation of terpenoids compounds as major compounds on methanol extract of pseudostems and rhizomes. Isolation and LC-MS/MS analysis identified 5-hydro-7, 8, 2'-trimethoxyflavanone (9), (E)-hexadecyl-ferulate (1), isocyperol (2), N-isobutyl-(2E,4E)-octadecadienamide (3), and nootkatone (4) from the rhizome extract, as well as from the leaves extract with the absence of 9. Three known steroid compounds, i.e., spinasterone (7), spinasterol (8), and 24-methylcholesta-7-en-3ß-on (6), were further identified from the pseudostem extract. Molecular docking showed that steroids compounds 7, 8, and 6 have lower predictive binding energies (MMGBSA) than other metabolites with binding energy of -87.91, -78.11, and -68.80 kcal/mole, respectively. Further characterization on the single isolated compound by NMR showed that 6 was identified and possessed 75% inhibitory activity on SARS-CoV-2 3CL protease enzyme that was slightly different with the positive control GC376 (77%). MD simulations showed the complex stability with compound 6 during 100 ns simulation time.


Assuntos
COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/farmacologia , Gengibre/química , Extratos Vegetais/farmacologia , Proteases 3C de Coronavírus/metabolismo , Proteases 3C de Coronavírus/ultraestrutura , Inibidores de Protease de Coronavírus/química , Inibidores de Protease de Coronavírus/isolamento & purificação , Inibidores de Protease de Coronavírus/uso terapêutico , Cristalografia por Raios X , Ensaios Enzimáticos , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Espectroscopia de Ressonância Magnética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Pirrolidinas/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , Relação Estrutura-Atividade , Ácidos Sulfônicos/farmacologia
7.
Molecules ; 26(17)2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34500777

RESUMO

Human neutrophil elastase (HNE) is a uniquely destructive serine protease with the ability to unleash a wave of proteolytic activity by destroying the inhibitors of other proteases. Although this phenomenon forms an important part of the innate immune response to invading pathogens, it is responsible for the collateral host tissue damage observed in chronic conditions such as chronic obstructive pulmonary disease (COPD), and in more acute disorders such as the lung injuries associated with COVID-19 infection. Previously, a combinatorially selected activity-based probe revealed an unexpected substrate preference for oxidised methionine, which suggests a link to oxidative pathogen clearance by neutrophils. Here we use oxidised model substrates and inhibitors to confirm this observation and to show that neutrophil elastase is specifically selective for the di-oxygenated methionine sulfone rather than the mono-oxygenated methionine sulfoxide. We also posit a critical role for ordered solvent in the mechanism of HNE discrimination between the two oxidised forms methionine residue. Preference for the sulfone form of oxidised methionine is especially significant. While both host and pathogens have the ability to reduce methionine sulfoxide back to methionine, a biological pathway to reduce methionine sulfone is not known. Taken together, these data suggest that the oxidative activity of neutrophils may create rapidly cleaved elastase "super substrates" that directly damage tissue, while initiating a cycle of neutrophil oxidation that increases elastase tissue damage and further neutrophil recruitment.


Assuntos
Imunidade Inata , Elastase de Leucócito/metabolismo , Metionina/análogos & derivados , Neutrófilos/imunologia , Biocatálise , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Domínio Catalítico/genética , Ensaios Enzimáticos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Elastase de Leucócito/antagonistas & inibidores , Elastase de Leucócito/genética , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Metionina/metabolismo , Simulação de Dinâmica Molecular , Infiltração de Neutrófilos , Neutrófilos/enzimologia , Oxirredução/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/patologia , SARS-CoV-2/imunologia , Especificidade por Substrato/imunologia
8.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502033

RESUMO

The novel coronavirus disease, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), rapidly spreading around the world, poses a major threat to the global public health. Herein, we demonstrated the binding mechanism of PF-07321332, α-ketoamide, lopinavir, and ritonavir to the coronavirus 3-chymotrypsin-like-protease (3CLpro) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CLpro with PF-07321332, α-ketoamide, lopinavir, and ritonavir revealed that 3CLpro-PF-07321332 and 3CLpro-α-ketoamide complexes remained stable compared with 3CLpro-ritonavir and 3CLpro-lopinavir. Investigating the dynamic behavior of ligand-protein interaction, ligands PF-07321332 and α-ketoamide showed stronger bonding via making interactions with catalytic dyad residues His41-Cys145 of 3CLpro. Lopinavir and ritonavir were unable to disrupt the catalytic dyad, as illustrated by increased bond length during the MD simulation. To decipher the ligand binding mode and affinity, ligand interactions with SARS-CoV-2 proteases and binding energy were calculated. The binding energy of the bespoke antiviral PF-07321332 clinical candidate was two times higher than that of α-ketoamide and three times than that of lopinavir and ritonavir. Our study elucidated in detail the binding mechanism of the potent PF-07321332 to 3CLpro along with the low potency of lopinavir and ritonavir due to weak binding affinity demonstrated by the binding energy data. This study will be helpful for the development and optimization of more specific compounds to combat coronavirus disease.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/farmacologia , Lactamas/farmacologia , Leucina/farmacologia , Nitrilas/farmacologia , Prolina/farmacologia , Antivirais/uso terapêutico , Domínio Catalítico/efeitos dos fármacos , Proteases 3C de Coronavírus/metabolismo , Inibidores de Protease de Coronavírus/uso terapêutico , Humanos , Lactamas/uso terapêutico , Leucina/uso terapêutico , Lopinavir/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nitrilas/uso terapêutico , Prolina/uso terapêutico , Ritonavir/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia
9.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34502041

RESUMO

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak in December 2019 has caused a global pandemic. The rapid mutation rate in the virus has created alarming situations worldwide and is being attributed to the false negativity in RT-PCR tests. It has also increased the chances of reinfection and immune escape. Recently various lineages namely, B.1.1.7 (Alpha), B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.617.3 have caused rapid infection around the globe. To understand the biophysical perspective, we have performed molecular dynamic simulations of four different spikes (receptor binding domain)-hACE2 complexes, namely wildtype (WT), Alpha variant (N501Y spike mutant), Kappa (L452R, E484Q) and Delta (L452R, T478K), and compared their dynamics, binding energy and molecular interactions. Our results show that mutation has caused significant increase in the binding energy between the spike and hACE2 in Alpha and Kappa variants. In the case of Kappa and Delta variants, the mutations at L452R, T478K and E484Q increased the stability and intra-chain interactions in the spike protein, which may change the interaction ability of neutralizing antibodies to these spike variants. Further, we found that the Alpha variant had increased hydrogen interaction with Lys353 of hACE2 and more binding affinity in comparison to WT. The current study provides the biophysical basis for understanding the molecular mechanism and rationale behind the increase in the transmissivity and infectivity of the mutants compared to wild-type SARS-CoV-2.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/transmissão , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/ultraestrutura , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/metabolismo , COVID-19/virologia , Cristalografia por Raios X , Humanos , Simulação de Dinâmica Molecular , Mutação , Estabilidade Proteica , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/ultraestrutura , Termodinâmica
10.
Braz J Biol ; 83: e247604, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34495156

RESUMO

In the current report, we studied the possible inhibitors of COVID-19 from bioactive constituents of Centaurea jacea using a threefold approach consisting of quantum chemical, molecular docking and molecular dynamic techniques. Centaurea jacea is a perennial herb often used in folk medicines of dermatological complaints and fever. Moreover, anticancer, antioxidant, antibacterial and antiviral properties of its bioactive compounds are also reported. The Mpro (Main proteases) was docked with different compounds of Centaurea jacea through molecular docking. All the studied compounds including apigenin, axillarin, Centaureidin, Cirsiliol, Eupatorin and Isokaempferide, show suitable binding affinities to the binding site of SARS-CoV-2 main protease with their binding energies -6.7 kcal/mol, -7.4 kcal/mol, -7.0 kcal/mol, -5.8 kcal/mol, -6.2 kcal/mol and -6.8 kcal/mol, respectively. Among all studied compounds, axillarin was found to have maximum inhibitor efficiency followed by Centaureidin, Isokaempferide, Apigenin, Eupatorin and Cirsiliol. Our results suggested that axillarin binds with the most crucial catalytic residues CYS145 and HIS41 of the Mpro, moreover axillarin shows 5 hydrogen bond interactions and 5 hydrophobic interactions with various residues of Mpro. Furthermore, the molecular dynamic calculations over 60 ns (6×106 femtosecond) time scale also shown significant insights into the binding effects of axillarin with Mpro of SARS-CoV-2 by imitating protein like aqueous environment. From molecular dynamic calculations, the RMSD and RMSF computations indicate the stability and dynamics of the best docked complex in aqueous environment. The ADME properties and toxicity prediction analysis of axillarin also recommended it as safe drug candidate. Further, in vivo and in vitro investigations are essential to ensure the anti SARS-CoV-2 activity of all bioactive compounds particularly axillarin to encourage preventive use of Centaurea jacea against COVID-19 infections.


Assuntos
COVID-19 , Centaurea , Preparações Farmacêuticas , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases , SARS-CoV-2
11.
PLoS One ; 16(9): e0256834, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34499662

RESUMO

The current pandemic outbreak clearly indicated the urgent need for tools allowing fast predictions of bioactivity of a large number of compounds, either available or at least synthesizable. In the computational chemistry toolbox, several such tools are available, with the main ones being docking and structure-activity relationship modeling either by classical linear QSAR or Machine Learning techniques. In this contribution, we focus on the comparison of the results obtained using different docking protocols on the example of the search for bioactivity of compounds containing N-N-C(S)-N scaffold at the S-protein of SARS-CoV-2 virus with ACE2 human receptor interface. Based on over 1800 structures in the training set we have predicted binding properties of the complete set of nearly 600000 structures from the same class using the Machine Learning Random Forest Regressor approach.


Assuntos
Antivirais/farmacologia , Aprendizado de Máquina , Simulação de Dinâmica Molecular , SARS-CoV-2/química , Tioureia/farmacologia , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Humanos , Ligação Proteica , Tioureia/química
12.
Nanoscale ; 13(30): 12916-12928, 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34477775

RESUMO

One of the most realistic approaches for delivering actives (pharmaceuticals/cosmetics) deep into skin layers is encapsulation into nanoparticles (NPs). Nonetheless, molecular-level mechanisms related to active delivery from NPs to the skin have scarcely been studied despite the large number of synthesis and characterization studies. We herein report the underlying mechanism of active translocation and permeation through the outermost layer of skin, the stratum corneum (SC), via molecular dynamics (MD) simulations complemented by experimental studies. A SC molecular model is constructed using current state-of-the-art methodology via incorporating the three most abundant skin lipids: ceramides, free fatty acids, and cholesterol. As a potent antioxidant, ferulic acid (FA) is used as the model active, and it is loaded into Gelucire 50/13 NP. MD simulations elucidate that, first, FA-loaded NP approaches the skin surface quickly, followed by slight penetration and adsorption onto the upper skin surface; FA then translocates from the NP surface to the skin surface due to stronger NP-skin interactions compared to the FA-NP interactions; then, once FA is released onto the skin surface, it slowly permeates deep into the skin bilayer. Both the free energy and resistance to permeation not only indicate the spontaneous transfer of FA from the bulk to the skin surface, but they also reveal that the main barrier against permeation exists in the middle of the lipid hydrophobic tails. Significantly lower diffusion of FA is obtained in the main barrier region compared to the bulk. The estimated permeability coefficient (log P) values are found to be higher than the experimental values. Importantly, the permeation process evaluated via MD simulations perfectly matches with experiments. The study suggests a molecular simulation platform that provides various crucial insights relating to active delivery from loaded NP to skin, and it could facilitate the design and development of novel NP-based formulations for transdermal delivery and the topical application of drugs/cosmetics.


Assuntos
Simulação de Dinâmica Molecular , Nanopartículas , Administração Cutânea , Bicamadas Lipídicas , Lipídeos , Permeabilidade , Pele
13.
Nanoscale ; 13(30): 13000-13013, 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34477783

RESUMO

Inorganic nanoparticles are gaining increasing attention as drug carriers because they respond to external physical stimuli, allowing therapy to be combined with diagnosis. Their drawback is low drug loading capacity, which can be improved by proper and efficacious functionalization. In this computational study, we take TiO2 spherical nanoparticles as prototype photoresponsive inorganic nanoparticles and we fully decorate them with two different types of bifunctional ligands: TETTs and DOPACs, which present different surface anchoring groups (silanol or catechol) but the same drug tethering COOH group, although in different concentrations (3 vs. 1), thus causing different steric hindrances. Then, we put these two types of nanocarriers in bulk water and in the presence of several DOX molecules and let the systems evolve through molecular dynamics (MD) simulations, clearly observing drug loading on the nanocarriers. This comparative MD study allows the investigation of the loading mechanism, performance of a conformational analysis and establishment of the guiding interactions through an energy decomposition analysis. We learn that DOX mostly interacts with the functionalized NPs through electrostatics, as a consequence of the protonated amino group, although several H-bonds are also established both with the ligands and with the oxide surface. Different ligands induce a different electrostatic potential around the NP; therefore, those which lead to the formation of more negative hotspots (here TETTs) are found to favour DOX binding. The leading role of electrostatics can provide a rational explanation for a pH-dependent drug release mechanism that is often invoked for DOX when reaching diseased cells because under anomalous acidic conditions both the NP surface and the carboxylate groups of the ligands are expected to get protonated, which of course would weaken, if not totally quench, the interaction of the nanocarrier with protonated DOX.


Assuntos
Doxorrubicina , Nanopartículas , Portadores de Fármacos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Simulação de Dinâmica Molecular
14.
Sci Rep ; 11(1): 17748, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493768

RESUMO

Based on WHO reports the new SARS-CoV-2 coronavirus is currently widespread all over the world. So far > 162 million cases have been confirmed, including > 3 million deaths. Because of the pandemic still spreading across the globe the accomplishment of computational methods to find new potential mechanisms of virus inhibitions is necessary. According to the fact that C60 fullerene (a sphere-shaped molecule consisting of carbon) has shown inhibitory activity against various protein targets, here the analysis of the potential binding mechanism between SARS-CoV-2 proteins 3CLpro and RdRp with C60 fullerene was done; it has resulted in one and two possible binding mechanisms, respectively. In the case of 3CLpro, C60 fullerene interacts in the catalytic binding pocket. And for RdRp in the first model C60 fullerene blocks RNA synthesis pore and in the second one it prevents binding with Nsp8 co-factor (without this complex formation, RdRp can't perform its initial functions). Then the molecular dynamics simulation confirmed the stability of created complexes. The obtained results might be a basis for other computational studies of 3CLPro and RdRp potential inhibition ways as well as the potential usage of C60 fullerene in the fight against COVID-19 disease.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Fulerenos/farmacologia , Antivirais/uso terapêutico , COVID-19/epidemiologia , COVID-19/virologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/ultraestrutura , Inibidores de Protease de Coronavírus/química , Inibidores de Protease de Coronavírus/farmacologia , Inibidores de Protease de Coronavírus/uso terapêutico , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , RNA-Polimerase RNA-Dependente de Coronavírus/ultraestrutura , Cristalografia por Raios X , Fulerenos/química , Fulerenos/uso terapêutico , Humanos , Simulação de Dinâmica Molecular , Inibidores da Síntese de Ácido Nucleico/química , Inibidores da Síntese de Ácido Nucleico/farmacologia , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Pandemias/prevenção & controle , RNA Viral/biossíntese , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/enzimologia , SARS-CoV-2/ultraestrutura
15.
Neuron ; 109(17): 2707-2716.e6, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34473954

RESUMO

The strychnine-sensitive pentameric glycine receptor (GlyR) mediates fast inhibitory neurotransmission in the mammalian nervous system. Only heteromeric GlyRs mediate synaptic transmission, as they contain the ß subunit that permits clustering at the synapse through its interaction with scaffolding proteins. Here, we show that α2 and ß subunits assemble with an unexpected 4:1 stoichiometry to produce GlyR with native electrophysiological properties. We determined structures in multiple functional states at 3.6-3.8 Å resolutions and show how 4:1 stoichiometry is consistent with the structural features of α2ß GlyR. Furthermore, we show that one single ß subunit in each GlyR gives rise to the characteristic electrophysiological properties of heteromeric GlyR, while more ß subunits render GlyR non-conductive. A single ß subunit ensures a univalent GlyR-scaffold linkage, which means the scaffold alone regulates the cluster properties.


Assuntos
Simulação de Dinâmica Molecular , Multimerização Proteica , Receptores de Glicina/química , Potenciais de Ação , Animais , Células HEK293 , Humanos , Bicamadas Lipídicas/metabolismo , Subunidades Proteicas , Receptores de Glicina/metabolismo , Células Sf9 , Spodoptera
16.
J Hazard Mater ; 416: 125966, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492878

RESUMO

Ammonia nitrogen and phenol are typical inorganic and organic pollutants in the coal chemical wastewater, respectively. In this study, the adsorption characteristics of ammonia nitrogen and phenol on lignite were investigated through experimental and molecular dynamics simulations. The results show that the adsorption of ammonia nitrogen was carried out via ion exchange, which was significantly faster than the adsorption of phenol driven by the π-π interaction. In the binary adsorption, the surface electronegativity of lignite decreased with the adsorption of ammonia nitrogen thereby promoting the adsorption of phenol. However, the extent of ammonia nitrogen adsorption was slightly reduced in the presence of phenol. Molecular dynamics simulation results indicated that the adsorption of phenol molecules on the lignite surface was closer than that of ammonium ion. The addition of ammonium ions could enhance the adsorption of phenol molecules on the lignite surface. The simulation results were well consistent with the experimental findings. This study indicates lignite has a promising potential in coal chemical wastewater adsorption pretreatment.


Assuntos
Amônia , Carvão Mineral , Adsorção , Amônia/análise , Simulação de Dinâmica Molecular , Nitrogênio , Fenol , Fenóis
17.
J Hazard Mater ; 416: 125976, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492884

RESUMO

The molecular-scale adsorption mechanism of heavy metal ions in the interlayer and nanopore regions of montmorillonite (MMT) were investigated by molecular dynamics simulations. Three typical heavy metals (zinc, cadmium, and lead) were selected as the model ions, and two types of MMT (Arizona and Wyoming) were considered. The results showed that Cd2+ and Pb2+ can form both inner- and outer-sphere complexes on Wyoming MMT, while Zn2+ only formed outer-sphere complex due to the stronger hydration interaction of Zn2+ than Cd2+ and Pb2+. For Arizona MMT, all of the three ions only formed outer-sphere complexes on its interlayer and external basal surface in which the cations remained a fully hydrated state. The calculated diffusion coefficients of three cations in interlayer and nanopore indicated that their diffusion abilities were significantly impaired, implying that MMT adsorbents have a strong ability to fix and retard heavy metal ions. The derived results and mechanisms are instrumental to a profound understanding of the transport and retention of heavy metal elements in subsurface environments, and provide guidance for the management of heavy metal pollution.


Assuntos
Metais Pesados , Nanoporos , Adsorção , Bentonita , Cádmio , Íons , Simulação de Dinâmica Molecular
18.
J Hazard Mater ; 416: 126116, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492911

RESUMO

Galaxolide (HHCB), one of the most widely used synthetic musks in personal care products (PCPs), has been recognized as an emerging contaminant with potential human health concerns. To overcome such adverse effects, a systematic molecular design, screening and performance evaluation approach was developed to generate functionally improved and environmentally friendly HHCB derivatives. Among the 90 designed HHCB derivatives, 15 were screened with improved functional properties (i.e., odor stability and intensity) and less environmental impacts (i.e., lower bio-toxicity, bio-accumulation ability, and mobility) using 3D-QSAR models and density functional theory methods. Their human health risks were then assessed by toxicokinetic analysis, which narrowed the candidates to four. Derivative 7, the designed molecule with the least dermal adsorption potential, was evaluated for its interaction with other PCPs additives (i.e., anti-photosensitivity materials and moisturizer) and such impacts on human health risks using molecular docking and molecular dynamic simulation. The environmental fate of Derivative 7 after transformation (i.e., photodegradation, biotransformation, and chlorination) was also discussed. Biotransformation and chlorination were recognized as optimum options for Derivative 7 mitigation. This study provided the theoretical basis for the design of functionally improved and environmentally friendly HHCB alternatives and advanced the understanding of their environmental behaviors and health risks.


Assuntos
Cosméticos , Relação Quantitativa Estrutura-Atividade , Benzopiranos , Biotransformação , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular
19.
Chem Commun (Camb) ; 57(72): 9096-9099, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34498651

RESUMO

We present a detailed computational analysis of the binding mode and reactivity of the novel oral inhibitor PF-07321332 developed against the SARS-CoV-2 3CL protease. Alchemical free energy calculations suggest that positions P3 and P4 could be susceptible to improvement in order to get a larger binding strength. QM/MM simulations unveil the reaction mechanism for covalent inhibition, showing that the nitrile warhead facilitates the recruitment of a water molecule for the proton transfer step.


Assuntos
Proteases 3C de Coronavírus/antagonistas & inibidores , Simulação de Dinâmica Molecular , Nitrilas/química , Inibidores de Proteases/química , SARS-CoV-2/enzimologia , Sítios de Ligação , COVID-19/patologia , COVID-19/virologia , Domínio Catalítico , Proteases 3C de Coronavírus/metabolismo , Humanos , Lactamas/química , Lactamas/metabolismo , Leucina/química , Leucina/metabolismo , Nitrilas/metabolismo , Prolina/química , Prolina/metabolismo , Inibidores de Proteases/metabolismo , Teoria Quântica , SARS-CoV-2/isolamento & purificação , Termodinâmica
20.
Comput Biol Med ; 136: 104692, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34333227

RESUMO

COVID-19, a newly discovered type of coronavirus, is the cause of the pandemic infection that was first reported in Wuhan, China, in December 2019. One of the most critical problems in this regard is to identify innovative drugs that may reduce or manage this global health concern. Nanoparticles have shown a pivotal role in drug delivery systems in recent decades. The surface of nanoparticles could be covered by a layer composed of different biomolecules (e.g., proteins and macromolecules) following the incubation with a biological fluid. This protein-rich layer is called "Protein Corona." In this study, an all-atom molecular dynamics simulation was used for investigating the monomeric B domain of the spike glycoprotein due to its role in the accessibility of the spike glycoprotein to single-wall carbon nanotubes (SWCNTs). The interaction energy values between the carbon nanotube and B domain of the viral spike glycoprotein were evaluated. The obtained results, based on Lennard-Jones potentials, demonstrated that SWCNTs had an affinity to the B domain of the S1 subunit in the spike glycoprotein. The adsorption of SWCNTs on the B domain surface led to a significant change in solvent-accessible surface, internal hydrogen bonds, and finally in the tertiary structure, which could provide a reasonable method to impede the interaction between the angiotensin-converting enzyme II and SARS-CoV-2 spike glycoprotein. A decrease in the mean square displacement of the B domain was shown after the adsorption of SWCNTs as a result of increasing the hydrophobic-hydrophilic properties of the B domain. The arrangement of SWCNTs on the B domain surface and their interaction using the 2-acetamido-2-deoxy-ß-d-glucopyranose group (988, 991, and 992) demonstrated that a change in the affinity of the S1 subunit could be used as a barrier to viral replication. The analysis of the SWCNT-B domain complex indicated that the presence of SWCNTs is able to cause alterations in the S1 subunit of the spike protein, and these nanotubes could be employed for further in-vitro and in-vivo antiviral studies. Also, SWCNTs are able to be utilized in drug delivery systems.


Assuntos
Nanotubos de Carbono , Glicoproteína da Espícula de Coronavírus/química , Simulação de Dinâmica Molecular , Ligação Proteica , SARS-CoV-2
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...