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1.
Ecotoxicol Environ Saf ; 203: 111046, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888614

RESUMO

Agricultural pesticides serve as effective controls of unwanted weeds and pests. However, these same chemicals can exert toxic effects in non-target organisms. To determine chemical modes of action, the toxicity ratio (TR) and critical body residues (CBRs) of 57 pesticides were calculated for Daphnia magna. Results showed that the CBR values of inert compounds were close to a constant while the CBR values of pesticides varied over a wider range. Although herbicides are categorized as specifically-acting compounds to plants, herbicides did not exhibit excess toxicity to Daphnia magna and were categorized as inert compounds with an average logTR = 0.41, which was less than a threshold of one. Conversely, fungicides and insecticides exhibited strong potential for toxic effects to Daphnia magna with an average logTR >2. Many of these chemicals act via disruption of the nervous, respiratory, or reproductive system, with high ligand-receptor binding activity which leads to higher toxicity for Daphnia magna. Molecular docking using acetylcholinesterase revealed that fungicides and insecticides bind more easily with the biological macromolecule when compared with inert compounds. Quantitative structure-activity relationship (QSAR) analysis revealed that the toxicity of fungicides was mainly dependent upon the heat of formation and polar surface area, while the toxicity of insecticides was more related to hydrogen-bond properties. This comprehensive analysis reveals that there are specific differences in toxic mechanisms between fungicides and insecticides. These results are useful for determining relative risk associated with pesticide exposure to aquatic crustaceans, such as Daphnia magna.


Assuntos
Daphnia/efeitos dos fármacos , Modelos Biológicos , Praguicidas/química , Praguicidas/toxicidade , Poluentes Químicos da Água/química , Poluentes Químicos da Água/toxicidade , Acetilcolinesterase/metabolismo , Animais , Daphnia/metabolismo , Relação Dose-Resposta a Droga , Fungicidas Industriais/química , Fungicidas Industriais/toxicidade , Herbicidas/química , Herbicidas/toxicidade , Ligação de Hidrogênio , Inseticidas/química , Inseticidas/toxicidade , Simulação de Acoplamento Molecular , Resíduos de Praguicidas/metabolismo , Relação Quantitativa Estrutura-Atividade
2.
Yakugaku Zasshi ; 140(9): 1101-1106, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32879242

RESUMO

Organoselenium compounds have attracted significant interest because of their use as important reagents in organic syntheses and potential biological activities, necessitating the development of simple and general synthetic methods. This article reviews our studies to develop of copper-catalyzed C-Se bond formation reactions via cross coupling and C-H activation. A number of unsymmetrical and symmetrical diaryl selenides were synthesized via Se-arylation of diaryl diselenides or selenium powder with triarylbismuthanes under aerobic conditions, achieving moderate to excellent yields. When the reaction of triphenylbismuthane with elemental Se was monitored with gas chromatography, diphenyl diselenide and diphenyl selenide formation was confirmed. Subsequently, 1-pot 2-step reactions were performed under mild conditions to obtain 3-selanyl imidazo[1,2-a]pyridines from triarylbismuthanes and diimidazopyridyl diselenides, which were generated from imidazo[1,2-a]pyridines and Se powder, in good to excellent yields. It should be noted that all three aryl groups in the bismuth and both selanyl groups in the diaryl diselenide generated from the selenium source were transferred to the coupling products. Cu-catalyzed tandem cyclization of 2-(2-iodophenyl)imidazo[1,2-a]pyridines with selenium for the synthesis of benzo[b]selenophene-fused imidazo[1,2-a]pyridines is also described herein. The molecular structure of the tetracyclic compound features nearly coplanar rings, and the maximum absorption is red-shifted compared to those of imidazo[1,2-a]pyridine and benzoselenophene.


Assuntos
Carbono/química , Cobre/química , Hidrogênio/química , Compostos Organosselênicos/síntese química , Catálise , Ciclização , Ligação de Hidrogênio , Fenômenos de Química Orgânica
3.
Acta Crystallogr C Struct Chem ; 76(Pt 9): 874-882, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32887858

RESUMO

Five 2-aroyl-5-bromobenzo[b]furan-3-ol compounds (two of which are new) and four new 2-aroyl-5-iodobenzo[b]furan-3-ol compounds were synthesized starting from salicylic acid. The compounds were characterized by mass spectrometry and 1H NMR and 13C NMR spectroscopy. Single-crystal X-ray diffraction studies of four compounds, namely, (5-bromo-3-hydroxybenzofuran-2-yl)(4-fluorophenyl)methanone, C15H8BrFO3, (5-bromo-3-hydroxybenzofuran-2-yl)(4-chlorophenyl)methanone, C15H8BrClO3, (5-bromo-3-hydroxybenzofuran-2-yl)(4-bromophenyl)methanone, C15H8Br2O3, and (4-bromophenyl)(3-hydroxy-5-iodobenzofuran-2-yl)methanone, C15H8BrIO3, were also carried out. The compounds were tested for their in vitro cytotoxicity on the four human cancer cell lines KB, Hep-G2, Lu-1 and MCF7. Six compounds show good inhibiting abilities on Hep-G2 cells, with IC50 values of 1.39-8.03 µM.


Assuntos
Antineoplásicos/química , Benzofuranos/síntese química , Células Hep G2/química , Antineoplásicos/farmacologia , Benzofuranos/química , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Estrutura Molecular
4.
Acta Crystallogr C Struct Chem ; 76(Pt 9): 914-920, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32887863

RESUMO

The terpenoid (-)-Istanbulin A is a natural product isolated from Senecio filaginoides DC, one of the 270 species of Senecio (Asteraceae) which occurs in Argentina. The structure and absolute configuration of this compound [9a-hydroxy-3,4a,5-trimethyl-4a,6,7,8a,9,9a-hexahydro-4H,5H-naphtho[2,3-b]-furan-2,8-dione or (4S,5R,8R,10S)-1-oxo-8ß-hydroxy-10ßH-eremophil-7(11)-en-12,8ß-olide, C15H20O4] were determined by single-crystal X-ray diffraction studies. It proved to be a sesquiterpene lactone showing an eremophilanolide skeleton whose chirality is described as 4S,5R,8R,10S. Structural results were also in agreement with the one- and two-dimensional (1D and 2D) NMR and HR-ESI-MS data, and other complementary spectroscopic information. In addition, (-)-Istanbulin A is a polymorph of the previously reported form of (-)-Istanbulin A, form I; thus, the title compound is denoted form II or polymorph II. Structural data and a literature search allowed the chirality of Istanbulin A to be revisited. The antimicrobial and antifungal activities of (-)-Istanbulin A, form II, were evaluated in order to establish a reference for future comparisons and applications related to specific crystal forms of Istanbulins.


Assuntos
Antifúngicos/química , Furanos/química , Sesquiterpenos/química , Cristalografia por Raios X , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Estereoisomerismo
5.
Nat Commun ; 11(1): 4655, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938918

RESUMO

Purely organic room-temperature phosphorescence has attracted attention for bioimaging but can be quenched in aqueous systems. Here we report a water-soluble ultralong organic room-temperature phosphorescent supramolecular polymer by combining cucurbit[n]uril (CB[7], CB[8]) and hyaluronic acid (HA) as a tumor-targeting ligand conjugated to a 4-(4-bromophenyl)pyridin-1-ium bromide (BrBP) phosphor. The result shows that CB[7] mediated pseudorotaxane polymer CB[7]/HA-BrBP changes from small spherical aggregates to a linear array, whereas complexation with CB[8] results in biaxial pseudorotaxane polymer CB[8]/HA-BrBP which transforms to relatively large aggregates. Owing to the more stable 1:2 inclusion complex between CB[8] and BrBP and the multiple hydrogen bonds, this supramolecular polymer has ultralong purely organic RTP lifetime in water up to 4.33 ms with a quantum yield of 7.58%. Benefiting from the targeting property of HA, this supramolecular polymer is successfully applied for cancer cell targeted phosphorescence imaging of mitochondria.


Assuntos
Mitocôndrias/efeitos dos fármacos , Polímeros/química , Células A549 , Células HEK293 , Humanos , Ácido Hialurônico/química , Ligação de Hidrogênio , Medições Luminescentes , Microscopia Confocal , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Polímeros/metabolismo , Taxoides/química , Temperatura
6.
PLoS Comput Biol ; 16(9): e1008103, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956350

RESUMO

Highly coordinated water molecules are frequently an integral part of protein-protein and protein-ligand interfaces. We introduce an updated energy model that efficiently captures the energetic effects of these ordered water molecules on the surfaces of proteins. A two-stage method is developed in which polar groups arranged in geometries suitable for water placement are first identified, then a modified Monte Carlo simulation allows highly coordinated waters to be placed on the surface of a protein while simultaneously sampling amino acid side chain orientations. This "semi-explicit" water model is implemented in Rosetta and is suitable for both structure prediction and protein design. We show that our new approach and energy model yield significant improvements in native structure recovery of protein-protein and protein-ligand docking discrimination tests.


Assuntos
Sítios de Ligação/fisiologia , Simulação de Acoplamento Molecular , Ligação Proteica/fisiologia , Proteínas , Água , Algoritmos , Aminoácidos/química , Aminoácidos/metabolismo , Ligação de Hidrogênio , Ligantes , Método de Monte Carlo , Proteínas/química , Proteínas/metabolismo , Água/química , Água/metabolismo
7.
Nat Commun ; 11(1): 4784, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963245

RESUMO

Genomic integrity is threatened by cytotoxic DNA double-strand breaks (DSBs), which must be resolved efficiently to prevent sequence loss, chromosomal rearrangements/translocations, or cell death. Polymerase µ (Polµ) participates in DSB repair via the nonhomologous end-joining (NHEJ) pathway, by filling small sequence gaps in broken ends to create substrates ultimately ligatable by DNA Ligase IV. Here we present structures of human Polµ engaging a DSB substrate. Synapsis is mediated solely by Polµ, facilitated by single-nucleotide homology at the break site, wherein both ends of the discontinuous template strand are stabilized by a hydrogen bonding network. The active site in the quaternary Pol µ complex is poised for catalysis and nucleotide incoporation proceeds in crystallo. These structures demonstrate that Polµ may address complementary DSB substrates during NHEJ in a manner indistinguishable from single-strand breaks.


Assuntos
Quebras de DNA de Cadeia Dupla , DNA Polimerase Dirigida por DNA/química , DNA/química , Cristalografia por Raios X , Dano ao DNA , Reparo do DNA por Junção de Extremidades , DNA Ligase Dependente de ATP/metabolismo , Reparo do DNA , Proteínas de Ligação a DNA/química , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Conformação Proteica
8.
Eur Rev Med Pharmacol Sci ; 24(14): 7834-7844, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32744711

RESUMO

The pandemic threat of COVID-19 causes serious concern for people and world organizations. The effect of Coronavirus disease on the lifestyle and economic status of humans is undeniable, and all of the researchers (biologists, pharmacists, physicians, and chemists) can help decrease its destructive effects. The molecular docking approach can provide a fast prediction of the positive influence the targets on the COVID-19 outbreak. In this work, we choose resveratrol (RV) derivatives (22 cases) and two newly released coordinate structures for COVID-19 as receptors [Papain-like Protease of SARS CoV-2 (PBD ID: 6W9C) and 2019-nCoV RNA-dependent RNA Polymerase (PBD ID: 6M71)]. The results show that conformational isomerism is significant and useful parameter for docking results. A wide spectrum of interactions such as Van der Waals, conventional hydrogen bond, Pi-donor hydrogen bond, Pi-Cation, Pi-sigma, Pi-Pi stacked, Amide-Pi stacked and Pi-Alkyl is detected via docking of RV derivatives and COVID-19 receptors. The potential inhibition effect of RV-13 (-184.99 kj/mol), and RV-12 (-173.76 kj/mol) is achieved at maximum value for 6W9C and 6M71, respectively.


Assuntos
Antivirais/metabolismo , Betacoronavirus/metabolismo , Papaína/metabolismo , RNA Replicase/metabolismo , Resveratrol/metabolismo , Vírus da SARS/metabolismo , Proteínas não Estruturais Virais/metabolismo , Antivirais/química , Antivirais/uso terapêutico , Betacoronavirus/isolamento & purificação , Sítios de Ligação , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Cristalografia por Raios X , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Pandemias , Papaína/química , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Estrutura Terciária de Proteína , RNA Replicase/química , Resveratrol/química , Resveratrol/uso terapêutico , Vírus da SARS/isolamento & purificação , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia , Proteínas não Estruturais Virais/química
9.
Acta Crystallogr C Struct Chem ; 76(Pt 8): 723-733, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32756034

RESUMO

The present study examines a series of six biologically-active flavonoid and chromanone derivatives by X-ray crystal structure analysis: (E)-3-benzylidene-2-phenylchroman-4-one, C22H16O2, I, (E)-3-(4-methylbenzylidene)-2-phenylchroman-4-one, C23H18O2, II, (E)-3-(3-methylbenzylidene)-2-phenylchroman-4-one, C23H18O2, III, (E)-3-(4-methoxybenzylidene)-2-phenylchroman-4-one, C23H18O3, IV, (E)-3-benzylidenechroman-4-one, C16H12O2, V, and (E)-3-(4-methoxybenzylidene)chroman-4-one, C17H14O3, VI. The cytotoxic activities of the presented crystal structures have been determined, together with their intermolecular interaction preferences and Hirshfeld surface characteristics. An inverse relationship was found between the contribution of C...C close contacts to the Hirshfeld surface and cytotoxic activity against the WM-115 cancer line. Dependence was also observed between the logP value and the percentage contribution of C...H contacts to the Hirshfeld surface.


Assuntos
Antineoplásicos/farmacologia , Cromanos/química , Citotoxinas/farmacologia , Flavonoides/química , Antineoplásicos/química , Cristalografia por Raios X , Citotoxinas/química , Ligação de Hidrogênio
10.
Acta Crystallogr C Struct Chem ; 76(Pt 8): 795-809, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32756043

RESUMO

The crystal structures of four new chiral [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines are described, namely, ethyl 5'-benzoyl-5'H,7'H-spiro[cyclohexane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate, C19H22N4O3S, ethyl 5'-(4-methoxybenzoyl)-5'H,7'H-spiro[cyclohexane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate, C20H24N4O4S, ethyl 6,6-dimethyl-5-(4-methylbenzoyl)-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C17H20N4O3S, and ethyl 5-benzoyl-6-(4-methoxyphenyl)-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C21H20N4O4S. The crystallographic data and cell activities of these four compounds and of the structures of three previously reported similar compounds, namely, ethyl 5'-(4-methylbenzoyl)-5'H,7'H-spiro[cyclopentane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate, C19H22N4O3S, ethyl 5'-(4-methoxybenzoyl)-5'H,7'H-spiro[cyclopentane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate, C19H22N4O4S, and ethyl 6-methyl-5-(4-methylbenzoyl)-6-phenyl-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C22H22N4O3S, are contrasted and compared. For both crystallization and an MTT assay, racemic mixtures of the corresponding [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines were used. The main manner of molecular packing in these compounds is the organization of either enantiomeric pairs or dimers. In both cases, the formation of two three-centre hydrogen bonds can be detected resulting from intramolecular N-H...O and intermolecular N-H...O or N-H...N interactions. Molecules of different enantiomeric forms can also form chains through N-H...O hydrogen bonds or form layers between which only weak hydrophobic contacts exist. Unlike other [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines, ethyl 5'-benzoyl-5'H,7'H-spiro[cyclohexane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate contains molecules of only the (R)-enantiomer; moreover, the N-H group does not participate in any significant intermolecular interactions. Molecular mechanics methods (force field OPLS3e) and the DFT B3LYP/6-31G+(d,p) method show that the compound forming enantiomeric pairs via weak N-H...N hydrogen bonds is subject to greater distortion of the geometry under the influence of the intermolecular interactions in the crystal. For intramolecular N-H...O and S...O interactions, an analysis of the noncovalent interactions (NCIs) was carried out. The cellular activities of the compounds were tested by evaluating their antiproliferative effect against two normal human cell lines and two cancer cell lines in terms of half-maximum inhibitory concentration (IC50). Some derivatives have been found to be very effective in inhibiting the growth of Hela cells at nanomolar and submicromolar concentrations with minimal cytotoxicity in relation to normal cells.


Assuntos
Cicloexanos/química , Compostos Heterocíclicos/farmacologia , Tiadiazinas/química , Cristalografia por Raios X , Células HeLa , Compostos Heterocíclicos/química , Humanos , Ligação de Hidrogênio , Conformação Molecular , Estereoisomerismo , Tiadiazinas/farmacologia
11.
J Mol Model ; 26(9): 231, 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32789582

RESUMO

The complement system plays a major role in human immunity, but its abnormal activation can have severe pathological impacts. By mimicking a natural mechanism of complement regulation, the small peptide compstatin has proven to be a very promising complement inhibitor. Over the years, several compstatin analogs have been created, with improved inhibitory potency. A recent analog is being developed as a candidate drug against several pathological conditions, including COVID-19. However, the reasons behind its higher potency and increased binding affinity to complement proteins are not fully clear. This computational study highlights the mechanistic properties of several compstatin analogs, thus complementing previous experimental studies. We perform molecular dynamics simulations involving six analogs alone in solution and two complexes with compstatin bound to complement component 3. These simulations reveal that all the analogs we consider, except the original compstatin, naturally adopt a pre-bound conformation in solution. Interestingly, this set of analogs adopting a pre-bound conformation includes analogs that were not known to benefit from this behavior. We also show that the most recent compstatin analog (among those we consider) forms a stronger hydrogen bond network with its complement receptor than an earlier analog.


Assuntos
Antivirais/química , Complemento C3/antagonistas & inibidores , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Antivirais/metabolismo , Complemento C3/metabolismo , Infecções por Coronavirus/tratamento farmacológico , Humanos , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Relação Estrutura-Atividade
12.
PLoS One ; 15(8): e0237300, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32785274

RESUMO

The outbreak of COVID-19 across the world has posed unprecedented and global challenges on multiple fronts. Most of the vaccine and drug development has focused on the spike proteins and viral RNA-polymerases and main protease for viral replication. Using the bioinformatics and structural modelling approach, we modelled the structure of the envelope (E)-protein of novel SARS-CoV-2. The E-protein of this virus shares sequence similarity with that of SARS- CoV-1, and is highly conserved in the N-terminus regions. Incidentally, compared to spike proteins, E proteins demonstrate lower disparity and mutability among the isolated sequences. Using homology modelling, we found that the most favorable structure could function as a gated ion channel conducting H+ ions. Combining pocket estimation and docking with water, we determined that GLU 8 and ASN 15 in the N-terminal region were in close proximity to form H-bonds which was further validated by insertion of the E protein in an ERGIC-mimic membrane. Additionally, two distinct "core" structures were visible, the hydrophobic core and the central core, which may regulate the opening/closing of the channel. We propose this as a mechanism of viral ion channeling activity which plays a critical role in viral infection and pathogenesis. In addition, it provides a structural basis and additional avenues for vaccine development and generating therapeutic interventions against the virus.


Assuntos
Betacoronavirus/química , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/genética , Betacoronavirus/isolamento & purificação , Simulação por Computador , Infecções por Coronavirus/virologia , Humanos , Hidrogênio , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Pneumonia Viral/virologia , Mutação Puntual , Conformação Proteica , Homologia Estrutural de Proteína , Vacinas Atenuadas , Vacinas de Produtos Inativados , Proteínas do Envelope Viral/imunologia , Vacinas Virais , Água/química
13.
J Chem Phys ; 153(7): 075101, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32828084

RESUMO

In 2020, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people worldwide and caused the coronavirus disease 2019 (COVID-19). Spike (S) glycoproteins on the viral membrane bind to ACE2 receptors on the host cell membrane and initiate fusion, and S protein is currently among the primary drug target to inhibit viral entry. The S protein can be in a receptor inaccessible (closed) or accessible (open) state based on down and up positions of its receptor-binding domain (RBD), respectively. However, conformational dynamics and the transition pathway between closed to open states remain unexplored. Here, we performed all-atom molecular dynamics (MD) simulations starting from closed and open states of the S protein trimer in the presence of explicit water and ions. MD simulations showed that RBD forms a higher number of interdomain interactions and exhibits lower mobility in its down position than its up position. MD simulations starting from intermediate conformations between the open and closed states indicated that RBD switches to the up position through a semi-open intermediate that potentially reduces the free energy barrier between the closed and open states. Free energy landscapes were constructed, and a minimum energy pathway connecting the closed and open states was proposed. Because RBD-ACE2 binding is compatible with the semi-open state, but not with the closed state of the S protein, we propose that the formation of the intermediate state is a prerequisite for the host cell recognition.


Assuntos
Betacoronavirus/química , Glicoproteína da Espícula de Coronavírus/química , Sítios de Ligação , Ligação de Hidrogênio , Modelos Químicos , Simulação de Dinâmica Molecular , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Análise de Componente Principal , Ligação Proteica , Conformação Proteica , Domínios Proteicos , Receptores Virais/química , Receptores Virais/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Termodinâmica
14.
Nat Commun ; 11(1): 4137, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811827

RESUMO

The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Molecular understanding of SecR binding and activation is important for its therapeutic exploitation. We combined cryo-electron microscopy, molecular dynamics, and biochemical cross-linking to determine a 2.3 Å structure, and interrogate dynamics, of secretin bound to the SecR:Gs complex. SecR exhibited a unique organization of its extracellular domain (ECD) relative to its 7-transmembrane (TM) core, forming more extended interactions than other family members. Numerous polar interactions formed between secretin and the receptor extracellular loops (ECLs) and TM helices. Cysteine-cross-linking, cryo-electron microscopy multivariate analysis and molecular dynamics simulations revealed that interactions between peptide and receptor were dynamic, and suggested a model for initial peptide engagement where early interactions between the far N-terminus of the peptide and SecR ECL2 likely occur following initial binding of the peptide C-terminus to the ECD.


Assuntos
Subunidades alfa Gs de Proteínas de Ligação ao GTP/química , Simulação de Dinâmica Molecular , Receptores Acoplados a Proteínas-G/química , Receptores dos Hormônios Gastrointestinais/química , Secretina/química , Sequência de Aminoácidos , Animais , Sítios de Ligação/genética , Linhagem Celular , Cricetinae , Microscopia Crioeletrônica , Cristalografia por Raios X , Cisteína/química , Cisteína/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/ultraestrutura , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Insetos , Modelos Moleculares , Ligação Proteica , Domínios Proteicos/genética , Estrutura Secundária de Proteína , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Acoplados a Proteínas-G/ultraestrutura , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores dos Hormônios Gastrointestinais/ultraestrutura , Secretina/metabolismo
15.
Phys Chem Chem Phys ; 22(33): 18272-18283, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32756685

RESUMO

The COVID-19 pandemic poses a severe threat to human health with unprecedented social and economic disruption. Spike (S) glycoprotein in the SARS-CoV-2 virus is pivotal in understanding the virus anatomy, since it initiates the early contact with the ACE2 receptor in the human cell. The subunit S1 in chain A of S-protein has four structural domains: the receptor binding domain (RBD), the n-terminal domain (NTD) and two subdomains (SD1, SD2). We report details of the intra- and inter-molecular binding mechanism of RBD using density functional theory, including electronic structure, interatomic bonding and partial charge distribution. We identify five strong hydrogen bonds and analyze their roles in binding. This provides a pathway to a quantum-chemical understanding of the interaction between the S-protein and the ACE2 receptor with insights into the function of conserved features in the ACE2 receptor binding domain that could inform vaccine and drug development.


Assuntos
Betacoronavirus/química , Peptidil Dipeptidase A/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Sequência de Aminoácidos , Teoria da Densidade Funcional , Humanos , Ligação de Hidrogênio , Modelos Químicos , Peptidil Dipeptidase A/química , Ligação Proteica , Domínios Proteicos , Alinhamento de Sequência , Glicoproteína da Espícula de Coronavírus/química
16.
J Chromatogr A ; 1626: 461352, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32797832

RESUMO

In the present study, we characterize a famous Pirkle-type enantioselective stationary phase ((R,R)-Whelk-O1 from Regis Technologies) and an equivalent enantiomeric phase (ReproSil Chiral-NR from Dr. Maisch) in supercritical fluid chromatography (SFC) with carbon dioxide - methanol (90:10 v/v) mobile phase. First, the interactions contributing to retention are evaluated with a modified version of the solvation parameter model, comprising five Abraham descriptors (E, S, A, B, V), two additional descriptors to take account of molecular shape (flexibility F and globularity G), and two additional descriptors to take account of interactions with ionizable species (D- and D+). Linear solvation energy relationships (LSER) are established based on the retention of 212 achiral analytes. As expected, π-π interactions are the most significant to explain retention, while dipole-dipole, hydrogen bonding and ionic interactions with cationic species are of secondary importance. Secondly, the contributions of interactions to enantioseparations are discussed, based on the analysis of 79 racemates. Discriminant analyses (DA) were computed to gain some insight on retention mechanisms. The set of racemates is first divided between racemates eluted earlier than expected based on the LSER models, and those eluted later than expected. Small spherical molecules are more retained than expected, as they may better fit inside the cleft of the chiral selector. They are also most frequently resolved, probably for the same reason. Among the molecules that are less retained than expected, which are rather large and/or non-spherical, other features are favourable to enantiorecognition: π-electrons, dipoles and electron-donating properties. Contrary to the observations on other sorts of chiral selectors, flexibility was found to have no contribution on the enantiorecognition process.


Assuntos
Cromatografia com Fluido Supercrítico/métodos , Dióxido de Carbono/química , Análise Discriminante , Ligação de Hidrogênio , Íons , Metanol/química , Modelos Teóricos , Estereoisomerismo
17.
Int J Nanomedicine ; 15: 5203-5215, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801686

RESUMO

Introduction: Metformin is an ideal candidate to treat the liver tumor with insulin resistance because of its good performance in the treatment of type 2 diabetes and the advantage in cancer therapy. We aim to develop a delivery system with higher efficiency than free drug. Methods: Metformin-bovine serum albumin (met-BSA) nanoparticles (NPs) were prepared using the anti-solvent precipitation method with a stabilizer of BSA for particle growth. The therapeutic effect of the drug was tested by the insulin-resistant HepG2 cells and C57BL/6J mice at a glucose starvation condition. The interaction mechanism of the drug and the protein during the formation of the NPs was tested using a series of spectroscopy. Results: Metformin and BSA formed nonporous and spherical particles of about 200 nm with proper lognormal distribution and thermostability. The cellular uptake, as well as the anti-liver cancer activities of met-BSA, was enhanced dramatically compared with the free drug. The thermodynamic studies suggested that the weak binding of metformin to BSA was governed by hydrogen bonds and van der Waals forces. Moreover, the results of synchronous, circular dichroism (CD) and three-dimensional fluorescence demonstrated that the BSA skeleton and chromophore microenvironments were changed in the presence of metformin. Conclusion: Therefore, met-BSA has been proved as a simple yet effective therapeutic agent for cancer with insulin resistance, promising for future clinic translations in cancer treatment.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Resistência à Insulina , Metformina/farmacologia , Nanopartículas/administração & dosagem , Soroalbumina Bovina/farmacologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Dicroísmo Circular , Diabetes Mellitus Tipo 2 , Células Hep G2 , Humanos , Ligação de Hidrogênio , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Metformina/administração & dosagem , Metformina/química , Camundongos Endogâmicos C57BL , Nanopartículas/química , Soroalbumina Bovina/química , Termodinâmica , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Chromatogr A ; 1626: 461341, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32797822

RESUMO

The recognition and separation of polar chiral compounds are important technological challenges in separation science. Taking full advantage of the intrinsically chiral environment and multiple interactions featured by macrocycles, we designed the first example of porous methylated cyclodextrins-containing polymers (MP-CDPs) with three-dimensional (3D) chiral channels. The enantioselective recognition of (R)/(S)-1-phenylethylamine mixtures was realized with enantiomer excess (e.e.) >73% in only 3 min by using MP-CDPs as the adsorbent. The obtained MP-CDPs also serve as highly efficient liquid chromatographic stationary phases for separation of polar chiral compounds. The stationary phase can separate racemic alcohols and acids successfully. These chiral compounds can be separated within 8 min under normal-phase mode, and the resolution (RS) range from 1.76 to 3.00. Molecular simulations suggest that chiral recognition is a cooperative interaction based on multiple effects such as host-guest interaction, H-bond and size selection. These findings will provide novel chiral stationary phases for recognition and separation of polar chiral compounds in the fields of separation science and pharmaceutical industry.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Polímeros/química , beta-Ciclodextrinas/química , Álcoois/química , Ligação de Hidrogênio , Porosidade , Estereoisomerismo
19.
J Phys Chem Lett ; 11(17): 7058-7065, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32787328

RESUMO

The current pandemic demands a search for therapeutic agents against the novel coronavirus SARS-CoV-2. Here, we present an efficient computational strategy that combines machine learning (ML)-based models and high-fidelity ensemble docking studies to enable rapid screening of possible therapeutic ligands. Targeting the binding affinity of molecules for either the isolated SARS-CoV-2 S-protein at its host receptor region or the S-protein:human ACE2 interface complex, we screen ligands from drug and biomolecule data sets that can potentially limit and/or disrupt the host-virus interactions. Top scoring one hundred eighty-seven ligands (with 75 approved by the Food and Drug Administration) are further validated by all atom docking studies. Important molecular descriptors (2χn, topological surface area, and ring count) and promising chemical fragments (oxolane, hydroxy, and imidazole) are identified to guide future experiments. Overall, this work expands our knowledge of small-molecule treatment against COVID-19 and provides a general screening pathway (combining quick ML models with expensive high-fidelity simulations) for targeting several chemical/biochemical problems.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Antivirais/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligação de Hidrogênio , Conformação Proteica , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/metabolismo
20.
J Chromatogr A ; 1626: 461308, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32797813

RESUMO

The Wayne State University (WSU) experimental descriptor database is utilized to bench mark the current capability of the solvation parameter model for use as a quantitative structure-retention relationship tool for estimating retention in gas and reversed-phase liquid chromatography. The prediction error for the retention factors of varied compounds on six open-tubular columns for gas chromatography (Rtx-5 SIL MS, DB-35 ms, RtxCLPesticides, HP-88, HP-INNOWAX and SLB-IL76) and three packed columns for reversed-phase liquid chromatography (SunFire C18, XBridge Shield RP18, and XBridge Phenyl) is used to establish expectations related to current practices. Each column data set was divided into a training set for calibration and a test set for validation employing a roughly 1 to 2 split, such that each test set contained about 40 to 80 varied compounds. The average absolute error for the prediction of retention factors by gas chromatography varied from about 0.1 to 0.4 on the retention factor scale with the larger error typical of stationary phases ranked as the most polar (or cohesive). For reversed-phase liquid chromatography the average error for the prediction of retention factors was 0.3 to 0.5 and generally larger than for gas chromatography. Statistical filters where utilized to identify a group of polycyclic aromatic compounds without hydrogen-bonding functional groups with a larger prediction error on the SunFire C18 column than for other compounds of smaller size, flexible structure or containing hydrogen-bonding functional groups. The heterogeneity of the retention mechanism is speculated to be the main contribution to the prediction error for both gas and liquid chromatography using the solvation parameter model.


Assuntos
Cromatografia Gasosa/métodos , Cromatografia de Fase Reversa/métodos , Ligação de Hidrogênio , Cinética , Solventes/química
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