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1.
Spectrochim Acta A Mol Biomol Spectrosc ; 244: 118825, 2021 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-32866803

RESUMEN

Novel antiviral active molecule 2- [(4,6-diaminopyrimidin-2-yl)sulfanyl]-N-(4-fluoro- phenyl)acetamide has been synthesised and characterized by FT-IR and FT-Raman spectra. The equilibrium geometry, natural bond orbital calculations and vibrational assignments have been carried out using density functional B3LYP method with the 6-311G++(d,p) basis set. The complete vibrational assignments for all the vibrational modes have been supported by normal coordinate analysis, force constants and potential energy distributions. A detailed analysis of the intermolecular interactions has been performed based on the Hirshfeld surfaces. Drug likeness has been carried out based on Lipinski's rule and the absorption, distribution, metabolism, excretion and toxicity of the title molecule has been calculated. Antiviral potency of 2- [(4,6-diaminopyrimidin-2-yl)sulfanyl]-N-(4-fluoro-phenyl) acetamide has been investigated by docking against SARS-CoV-2 protein. The optimized geometry shows near-planarity between the phenyl ring and the pyrimidine ring. Differences in the geometries due to the substitution of the most electronegative fluorine atom and intermolecular contacts due to amino pyrimidine were analyzed. NBO analysis reveals the formation of two strong stable hydrogen bonded N-H···N intermolecular interactions and weak intramolecular interactions C-H···O and N-H···O. The Hirshfeld surfaces and consequently the 2D-fingerprint confirm the nature of intermolecular interactions and their quantitative contributions towards the crystal packing. The red shift in N-H stretching frequency exposed from IR substantiate the formation of N-H···N intermolecular hydrogen bond. Drug likeness and absorption, distribution, metabolism, excretion and toxicity properties analysis gives an idea about the pharmacokinetic properties of the title molecule. The binding energy -8.7 kcal/mol of the nonbonding interaction present a clear view that 2- [(4,6-diaminopyrimidin-2-yl)sulfanyl]-N-(4-fluoro- phenyl) acetamide can irreversibly interact with SARS-CoV-2 protease.


Asunto(s)
Antivirales/química , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Pandemias , Neumonía Viral/tratamiento farmacológico , Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/farmacocinética , Betacoronavirus/enzimología , Cristalografía por Rayos X , Cisteína Endopeptidasas , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Dinámicas no Lineales , Inhibidores de Proteasas/farmacocinética , Conformación Proteica , Teoría Cuántica , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría Raman , Termodinámica , Vibración
2.
Food Chem ; 343: 128497, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33160771

RESUMEN

The stability and bioavailability of fourteen astaxanthin esters (Asta-Es) with different molecular structures were investigated using in vitro and in vivo digestion models. The results demonstrated that Asta-E with long-chain and saturated fatty acids were more stable than other types of Asta-E. Astaxanthin diester (Asta-DE) was better than astaxanthin monoester (Asta-ME) and free astaxanthin (F-Asta), as determined based on the degradation rate constant at 60 °C. The absorbability of Asta-Es with different molecular structures was evaluated through the serum concentrations of astaxanthin (Asta). The results indicated that Asta-E with short-chain fatty acids had higher bioavailability than Asta-Es with long-chain fatty acids, whereas Asta-E with high-unsaturation fatty acids had higher bioavailability than Asta-E with low-unsaturation fatty acids. Asta-ME had significantly increased bioavailability compared with Asta-DE. We concluded that the molecular structure of Asta-E could significantly affect their stability and bioavailability.


Asunto(s)
Ésteres/química , Disponibilidad Biológica , Estabilidad de Medicamentos , Ácidos Grasos/química , Estructura Molecular , Xantófilas/química , Xantófilas/farmacocinética
3.
Proc Natl Acad Sci U S A ; 118(2)2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33361332

RESUMEN

Information about macromolecular structure of protein complexes and related cellular and molecular mechanisms can assist the search for vaccines and drug development processes. To obtain such structural information, we present DeepTracer, a fully automated deep learning-based method for fast de novo multichain protein complex structure determination from high-resolution cryoelectron microscopy (cryo-EM) maps. We applied DeepTracer on a previously published set of 476 raw experimental cryo-EM maps and compared the results with a current state of the art method. The residue coverage increased by over 30% using DeepTracer, and the rmsd value improved from 1.29 Å to 1.18 Å. Additionally, we applied DeepTracer on a set of 62 coronavirus-related cryo-EM maps, among them 10 with no deposited structure available in EMDataResource. We observed an average residue match of 84% with the deposited structures and an average rmsd of 0.93 Å. Additional tests with related methods further exemplify DeepTracer's competitive accuracy and efficiency of structure modeling. DeepTracer allows for exceptionally fast computations, making it possible to trace around 60,000 residues in 350 chains within only 2 h. The web service is globally accessible at https://deeptracer.uw.edu.


Asunto(s)
Aprendizaje Profundo , Modelos Estructurales , Estructura Molecular , Proteínas Virales/ultraestructura , Microscopía por Crioelectrón
4.
Proc Natl Acad Sci U S A ; 118(2)2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33361333

RESUMEN

The molecular basis for the severity and rapid spread of the COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. ORF8 is a rapidly evolving accessory protein that has been proposed to interfere with immune responses. The crystal structure of SARS-CoV-2 ORF8 was determined at 2.04-Šresolution by X-ray crystallography. The structure reveals a ∼60-residue core similar to SARS-CoV-2 ORF7a, with the addition of two dimerization interfaces unique to SARS-CoV-2 ORF8. A covalent disulfide-linked dimer is formed through an N-terminal sequence specific to SARS-CoV-2, while a separate noncovalent interface is formed by another SARS-CoV-2-specific sequence, 73YIDI76 Together, the presence of these interfaces shows how SARS-CoV-2 ORF8 can form unique large-scale assemblies not possible for SARS-CoV, potentially mediating unique immune suppression and evasion activities.


Asunto(s)
Estructura Molecular , Proteínas Virales/química , Evolución Molecular , Evasión Inmune
5.
Spectrochim Acta A Mol Biomol Spectrosc ; 247: 119082, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33120121

RESUMEN

With the global epidemic of the COVID-19 virus, extensive and rapid research on drug therapy is underway around the world. In this regard, one of the most widely studied drugs is Favipiravir. Our aim in this paper is to conduct comprehensive research based on the Density Functional Theory (DFT) on the potential of metallofullerenes as suitable drug carriers. The surface interaction of Favipiravir with organometallic compound resulted by doping of the five transition metals of the first row of the periodic table (Ti, Cr, Cr, Fe, Ni, and Zn) was examined in depth to select the most suitable metallofullerenes. First, the adsorption geometries of Favipiravir drug onto each metallofullerene were deeply investigated. It was found that Cr-, Fe-, and Ni-doped fullerenes provide the excellent adsorbent property with adsorption energies of -148.2, -149.6, and -146.6 kJ/mol, respectively. The Infrared spectroscopy (IR) study was conducted to survey the stretching vibration of bonds involving in the systems, specialty the CO in the drug, CM in the metallofullerene, and MO in the metallofullerene-drug complex. Finally, the UV-vis analysis showed that the absorption spectra for the studied systems may be attributed to the transition from π-π* and/or n-π*.


Asunto(s)
Amidas/química , Fulerenos/química , Pandemias , Pirazinas/química , /química , Amidas/uso terapéutico , Fulerenos/uso terapéutico , Humanos , Estructura Molecular , Pirazinas/uso terapéutico , Espectrofotometría Infrarroja
6.
Bioorg Med Chem Lett ; 31: 127667, 2021 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-33160024

RESUMEN

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) continues to spread worldwide, with 25 million confirmed cases and 800 thousand deaths. Effective treatments to target SARS-CoV-2 are urgently needed. In the present study, we have identified a class of cyclic sulfonamide derivatives as novel SARS-CoV-2 inhibitors. Compound 13c of the synthesized compounds exhibited robust inhibitory activity (IC50 = 0.88 µM) against SARS-CoV-2 without cytotoxicity (CC50 > 25 µM), with a selectivity index (SI) of 30.7. In addition, compound 13c exhibited high oral bioavailability (77%) and metabolic stability with good safety profiles in hERG and cytotoxicity studies. The present study identified that cyclic sulfonamide derivatives are a promising new template for the development of anti-SARS-CoV-2 agents.


Asunto(s)
Antivirales/farmacología , Descubrimiento de Drogas , Sulfonamidas/farmacología , Animales , Antivirales/síntesis química , Antivirales/química , Línea Celular , Chlorocebus aethiops , Cricetulus , Perros , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química
7.
Phytochemistry ; 181: 112537, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33099226

RESUMEN

The phytochemical exploration of the Entandrophragma candollei stem bark extract led to the isolation and identification of twenty compounds including three undescribed phragmalin-class limonoids named encandollens C-E (1-3), the undescribed protolimonoid 5 together with sixteen known compounds. The structures of all the isolated compounds were determined by interpretation of their spectroscopic and spectrometric data including HRMS, 1D and 2D NMR analyses. The assignment of the absolute and relative stereochemistry of the undescribed compounds was achieved using SC-XRD analyses as well as NOESY experiments. The previously reported structure of odoratone (5a) was corrected as 23 R,24 S-dihydroxy-22 S,25-epoxytirucall-7-en-3-one (5) based on its NMR and SC-XRD data. Prieurianin (4) exhibited high cytotoxic activity on KB3-1 cell lines with an IC50 of 1.47 µM compared to the reference griseofulvin (IC50 = 17-21 µM). The results of the in silico docking of compound 4 supported and delivered further insights on its cytotoxicity.


Asunto(s)
Limoninas , Meliaceae , Limoninas/farmacología , Estructura Molecular , Corteza de la Planta
8.
Phytochemistry ; 181: 112540, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33130371

RESUMEN

Aglaia is the largest genus in the Meliaceae family (also known as Mahagoni in Indonesia), consisting of over 150 species, of which 65 are indigenous to Indonesia. These species spread through the tropical regions, especially Southeast Asia as well as the Nothern part of Australia, and have been used in traditional medicine for the treatment of several diseases. However, preliminary chemical researches commenced in 1965, where dammarane-type triterpenoids, aglaiol was isolated, and the structure was determined by chemical reaction and spectroscopic methods. Several studies have been carried out on the stembark, bark, leaves, seeds and leaves in the last fifty five years, and about 291 metabolites have been isolated from the sesquiterpenoid, diterpenoid, triterpenoid, limonoid, steroid, lignan, and alkaloid groups, as well as flavagline, which known to be the largest. This specifically amounts to 34% of Aglaia species, reported to show cytotoxic and insecticidal potentials, and also the tendency for use as chemical markers for this species. The extracts and compounds obtained from Aglaia species are evaluated for potential biological activities, including cytotoxicity, insecticidal, anti-inflammatory, antifungal, molluscicidal, antituberculosis and antiviral effects. In addition, flavagline (rocaglamide) derivatives have been confirmed to exhibit exceptional cytotoxicity, and are, thus, considered lead compounds for further development. Therefore, the results support the concept of utilizing Aglaia species as a potential source for the production of biologically active compounds.


Asunto(s)
Aglaia , Productos Biológicos , Australia , Indonesia , Estructura Molecular
9.
Phytochemistry ; 181: 112555, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33142147

RESUMEN

Three previously undescribed limonoids, fulvifomins A-C, together with two known compounds, 6-deoxydetigloyl-swietenine acetate and methyl angolensate, were isolated from fruiting bodies of the wood-rot fungus Fulvifomes xylocarpicola (Hymenochaetaceae), growing on the mangrove tree Xylocarpus granatum (Meliaceae). The structures were elucidated on the basis of NMR spectroscopic and mass spectrometry data, and X-ray crystallographic analysis (for fulvifomin A). A number of similar limonoids have been isolated from higher plants of the family Meliaceae, including X. granatum. The present study represents a unique evidence that the associated basidiomycete also contains these limonoids. Fulvifomin B exhibited moderate antimalarial and antitubercular activites.


Asunto(s)
Basidiomycota , Limoninas , Meliaceae , Cuerpos Fructíferos de los Hongos , Limoninas/farmacología , Estructura Molecular , Árboles , Madera
10.
Phytochemistry ; 181: 112554, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33152579

RESUMEN

Six undescribed compounds, including three sesquiterpenoids [(4S,5S,7S,8S,11R)-7-hydroxyguai-1(10)-en-8,12-olide, aquilarisinone, and 2Z,7(13),9E-humulatrien-12-ol-5-one], one diphenylpentanone [1-(2-hydroxyphenyl)-5-phenylpentan-3-one], and two 2-(2-phenylethyl)chromones (6-epiagarotetrol and triepoxyhexahydrochromone A), along with 15 known compounds, were isolated from the resinous heartwood of Aquilaria sinensis (Thymelaeaceae). Their structures were determined by mass (MS) and nuclear magnetic resonance (NMR) spectroscopic data. The absolute configuration of (4S,5S,7S,8S,11R)-7-hydroxyguai-1(10)-en-8,12-olide was confirmed by X-ray diffraction analysis, and the configurations of (4S,7S,8S,10R,11R)-7,10-epoxyguai-1(5)-en-8,12-olide, aquilarisinone, 6-epiagarotetrol, and triepoxyhexahydrochromone A were confirmed by electronic circular dichroism (ECD) calculations. The neuroprotective activities of the compounds were evaluated using models of BACE1 inhibition and PC12 cells with corticosterone- and 1-methyl-4-phenylpyridine ion (MPP+)-induced damage. At concentrations of 1, 2, and 5 µM, triepoxyhexahydrochromone A, (+)-(7R,10R)-selina-4,11(13)-diene-12,15-dial, (-)-(5R,7R,10R)-12,15-dioxo-α-selinene, and (+)-(1R,4S,5R)-1ß-hydroxyeremophila-7(11),9-dien-8-one exerted significant protective effects (p < 0.01) on PC12 cell injury induced by corticosterone, while triepoxyhexahydrochromone A and (-)-(5R,7R,10R)-12,15-dioxo-α-selinene exerted significant protective effects (p < 0.01) on MPP+-induced PC12 cell injury at concentrations of 1, 2, and 5 µM. No compounds produced significant inhibitory effects on BACE1, with inhibition rates of less than 20% observed at a concentration of 20 µM.


Asunto(s)
Secretasas de la Proteína Precursora del Amiloide , Thymelaeaceae , Animales , Ácido Aspártico Endopeptidasas , Cromonas , Estructura Molecular , Ratas
11.
Phytochemistry ; 181: 112536, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33160226

RESUMEN

Seven undescribed indole-based alkaloids, xuefengins A-D and xuefenglasins A-C, were isolated from natural Ophiocordyceps xuefengensis, along with six known alkaloids. Their structures were elucidated by comprehensive spectroscopy, with absolute configurations confirmed by comparison with calculated electronic circular dichroism spectra. Eleven of the isolates were tested for cytotoxicity against the U937, NB4, MCF-7, Hep G2, and A549 cancer cell lines. Two compounds exhibited moderate activities, with IC50 values of 2.83-25.68 µM and 1.54-12.16 µM. Further pharmacological studies showed that these two compounds inhibit cell proliferation by inducing apoptosis, and decreasing p38 and caspase-3 levels in A549 cells.


Asunto(s)
Alcaloides , Alcaloides Indólicos , Células A549 , Alcaloides/farmacología , Línea Celular Tumoral , Hypocreales , Alcaloides Indólicos/farmacología , Estructura Molecular
12.
Phytochemistry ; 181: 112543, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33161176

RESUMEN

Seven undescribed terpenoids, including three pairs of enantiomers, named (±)-rugulolides A-C, and one cyclopentenone derivative, named rugulolide D, together with twenty-six known compounds, were isolated from the aerial parts of Elsholtzia rugulosa. The chiral separation of rugulolides A-C was achieved by high-performance liquid chromatography using the chiral column. Their structures were elucidated unambiguously based on comprehensive spectroscopic analysis in conjunction with electronic circular dichroism (ECD) and single-crystal X-ray diffraction experiments. Rugulolides A-D are rare naturally occurring terpenoid derivatives featuring a methylated α,ß-unsaturated-γ-lactone or a cyclopent-2-en-1-one nucleus. All the isolates were evaluated for their inhibitory effects on lipopolysaccharide-induced nitric oxide production in RAW264.7 cell, among them, four compounds showed moderate inhibition with IC50 values ranging from 12.46 to 23.10 µM.


Asunto(s)
Lamiaceae , Terpenos , Animales , Antiinflamatorios/farmacología , Ratones , Estructura Molecular , Componentes Aéreos de las Plantas , Terpenos/farmacología
13.
Phytochemistry ; 181: 112580, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33166752

RESUMEN

Thirteen undescribed 24-methylene lanostane triterpenoids, named polyporenic acids E-M and fomitosides L-O, as well as seventeen known analogues, were isolated from the fruiting bodies of the mushroom Fomitopsis betulina. Their structures were determined using 1D, 2D NMR, IR, and HRESIMS. Fomitoside L and fomitoside N exhibited cytotoxicity against HL60 leukemia cells (IC50 = 15.8 and 23.7 µM, respectively). Among the known compounds, notable cytotoxicities against HL60 leukemia cells and selectivity with respect to MRC-5 healthy cells were noticed for dehydropachymic acid (IC50 = 10.9 µM, SI 8.6), pachymic acid (IC50 = 11.0 µM, SI 9.8), 3-epi-dehydrotumulosic acid (IC50 = 19.9 µM, SI 5.8) and 12α-hydroxy-3α-(3'-hydroxy-4'-methoxycarbonyl-3'-methylbutyryloxy)-24-methyllanosta-8,24 (31)-dien-26-oic acid (IC50 = 19.2 µM, SI 2.2).


Asunto(s)
Agaricales , Triterpenos , Ésteres , Humanos , Estructura Molecular , Polyporales , Azúcares , Triterpenos/farmacología
14.
Phytochemistry ; 181: 112578, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33171341

RESUMEN

Twelve undescribed 2-(2-phenylethyl)chromone derivatives, including one pair of enantiomers, together with eleven known ones, were isolated from the EtOAc extract of agarwood originating from Aquilaria filaria. All structures were elucidated by spectroscopic (NMR, UV, IR, MS) methods and compared with reported data in literatures. Twenty-one compounds were assessed for α-glucosidase inhibitory activity, which showed inhibition of α-glucosidase with IC50 values ranging between 7.8 ± 0.3 to 137.7 ± 3.0 µM (Acarbose, 743.4 ± 3.3 µM; Genistein, 8.3 ± 0.1 µM). Our results expanded the structural diversity of 2-(2-phenylethyl)chromones from agarwood, and revealed the potential of 2-(2-phenylethyl)chromones as α-glucosidase inhibitors.


Asunto(s)
Inhibidores de Glicósido Hidrolasas , Thymelaeaceae , Cromonas/farmacología , Flavonoides , Inhibidores de Glicósido Hidrolasas/farmacología , Estructura Molecular
15.
Phytochemistry ; 181: 112567, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33197742

RESUMEN

Seven previously undescribed diterpenoid alkaloids, including five C20-diterpenoid alkaloids, barpuberudine, barpubesines A-D, and two C18-diterpenoid alkaloids, barpubenines A-B, along with 11 known diterpenoid alkaloids were isolated from the whole plant of Aconitum barbatum var. puberulum Ledeb. (Ranunculaceae). Barpuberudine is an unprecedented carbon skeleton of C20-diterpenoid alkaloid, while barpubenines A-B are the first example of rearranged types in C18-diterpenoid alkaloids. Their structures were elucidated based on a comprehensive spectroscopic data analysis. The probable pathway of biogenesis of barpuberudine and barpubenines A-B were discussed. Additionally, the antiarrhythmic, cytotoxic and antimicrobial activities of isolates were also evaluated.


Asunto(s)
Aconitum , Alcaloides , Alcaloides/farmacología , Diterpenos/farmacología , Estructura Molecular , Raíces de Plantas
16.
Phytochemistry ; 181: 112566, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33197743

RESUMEN

Fourteen undescribed monoterpenoid indole alkaloids, voacafrines A-N, along with 7 known monoterpenoid indole alkaloids were isolated from the seeds of Voacanga africana Stapf. Among them, voacafrines A-G were aspidosperma-aspidosperma type bisindole alkaloids, while voacafrines H-N were aspidosperma-type monomers. Their structures and absolute configurations were elucidated by a combination of NMR, MS, and ECD analyses. Voacafrines A-C were characterized by an acetonyl moiety at C-5', while voacafrine H possessed a methoxymethyl moiety at C-14 within aspidosperma-type alkaloids. The acetylcholinesterase (AChE) inhibitory activity and cytotoxicity of voacafrines A-N were evaluated. Voacafrines A-C and E-G were bisindole alkaloids that exhibited AChE inhibitory activity with IC50 values of 4.97-33.28 µM, while voacafrines I and J were monomers that showed cytotoxicity against several human cancer cell lines with IC50 values of 4.45-7.49 µM.


Asunto(s)
Aspidosperma , Alcaloides de Triptamina Secologanina , Voacanga , Alcaloides Indólicos/farmacología , Estructura Molecular , Alcaloides de Triptamina Secologanina/farmacología
17.
Acta Pharm ; 71(2): 175-184, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33151168

RESUMEN

Recently, an outbreak of a fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. Possible interaction of SARS-CoV-2 with DPP4 peptidase may partly contribute to the viral pathogenesis. An integrative bioinformatics approach starting with mining the biomedical literature for high confidence DPP4-protein/gene associations followed by functional analysis using network analysis and pathway enrichment was adopted. The results indicate that the identified DPP4 networks are highly enriched in viral processes required for viral entry and infection, and as a result, we propose DPP4 as an important putative target for the treatment of COVID-19. Additionally, our protein-chemical interaction networks identified important interactions between DPP4 and sitagliptin. We conclude that sitagliptin may be beneficial for the treatment of COVID-19 disease, either as monotherapy or in combination with other therapies, especially for diabetic patients and patients with pre-existing cardiovascular conditions who are already at higher risk of COVID-19 mortality.


Asunto(s)
Infecciones por Coronavirus/tratamiento farmacológico , Dipeptidil Peptidasa 4/efectos de los fármacos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Fosfato de Sitagliptina/farmacología , Fosfato de Sitagliptina/uso terapéutico , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/tratamiento farmacológico , Biología Computacional , Infecciones por Coronavirus/complicaciones , Cristalografía por Rayos X , Minería de Datos , Complicaciones de la Diabetes/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Reposicionamiento de Medicamentos , Redes Reguladoras de Genes , Humanos , Estructura Molecular , Pandemias , Neumonía Viral/complicaciones
18.
Acta Pharm ; 71(2): 163-174, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33151166

RESUMEN

The current outbreak of novel coronavirus (COVID-19) infections urges the need to identify potential therapeutic agents. Therefore, the repurposing of FDA-approved drugs against today's diseases involves the use of de-risked compounds with potentially lower costs and shorter development timelines. In this study, the recently resolved X-ray crystallographic structure of COVID-19 main protease (Mpro) was used to generate a pharmacophore model and to conduct a docking study to capture antiviral drugs as new promising COVID-19 main protease inhibitors. The developed pharmacophore successfully captured five FDA-approved antiviral drugs (lopinavir, remdesivir, ritonavir, saquinavir and raltegravir). The five drugs were successfully docked into the binding site of COVID-19 Mpro and showed several specific binding interactions that were comparable to those tying the co-crystallized inhibitor X77 inside the binding site of COVID-19 Mpro. Three of the captured drugs namely, remdesivir, lopinavir and ritonavir, were reported to have promising results in COVID-19 treatment and therefore increases the confidence in our results. Our findings suggest an additional possible mechanism of action for remdesivir as an antiviral drug inhibiting COVID-19 Mpro. Additionally, a combination of structure-based pharmacophore modeling with a docking study is expected to facilitate the discovery of novel COVID-19 Mpro inhibitors.


Asunto(s)
Infecciones por Coronavirus/enzimología , Neumonía Viral/enzimología , Inhibidores de Proteasas/farmacología , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/química , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/uso terapéutico , Alanina/análogos & derivados , Alanina/química , Alanina/farmacología , Alanina/uso terapéutico , Antivirales/química , Antivirales/farmacología , Infecciones por Coronavirus/tratamiento farmacológico , Cristalografía por Rayos X , Descubrimiento de Drogas/métodos , Reposicionamiento de Medicamentos , Humanos , Modelos Químicos , Simulación del Acoplamiento Molecular , Estructura Molecular , Pandemias , Neumonía Viral/tratamiento farmacológico , Inhibidores de Proteasas/química , Relación Estructura-Actividad
19.
Chemosphere ; 263: 127997, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32846289

RESUMEN

The environmental safety of flame retardants has attracted growing attention. Alkyl organophosphorus flame retardants (OPFRs) have been prevalently applied, but the potential risk and the structure effects of different alkyl chain lengths OPFRs on aquatic microalgae remain unknown. This study investigated the biological response of five alkyl-OPFRs to Chlorella pyrenoidosa by computational simulation together with biological approaches. The reduced docking energy had a significantly positive correlation (R2 = 0.9) with the cell inhibition alongside the incremental chain length of alkyl-OPFRs. Molecular docking simulations suggested that the toxicity of alkyl-OPFRs would be highly correlated to their molecular structures. Coincidently, the reactive oxygen species, superoxide dismutase and malondialdehyde were triggered by 85%, 92% and 155% (based on the control group), after exposure to the longest chain length tributyl phosphate (TBPC12), respectively. Furthermore, combining the ultrastructure scrutiny with the photosynthesis analysis, TBPC12 was also found to significantly inhibit the chlorophyll biosynthesis (43%) and restrain the photosynthetic efficiency (26%) when compared with the control group. Overall, this is the first study to comprehensively reveal the biological effects of different alkyl-OPFRs on microalgae via the combination of computational simulation and cellular responses, providing a novel insight into targeted predicting the aquatic ecological risks of OPFRs.


Asunto(s)
Chlorella/efectos de los fármacos , Retardadores de Llama/toxicidad , Organofosfatos/toxicidad , Productos Biológicos , Carbono , Retardadores de Llama/análisis , Simulación del Acoplamiento Molecular , Estructura Molecular , Compuestos Organofosforados/toxicidad , Especies Reactivas de Oxígeno
20.
PLoS One ; 15(12): e0243041, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33362250

RESUMEN

Alzheimer disease (AD) is a neurodegenerative disorder characterized by the aberrant production and accumulation of amyloid-ß (Aß) peptides in the brain. Accumulated Aß in soluble oligomer and insoluble plaque forms are considered to be a pathological culprit and biomarker of the disorder. Here, we report a fluorescent universal Aß-indicator YI-13, 5-(4-fluorobenzoyl)-7,8-dihydropyrrolo[1,2-b]isoquinolin-9(6H)-one, which detects Aß monomers, dimers, and plaques. We synthesized a library of 26 fluorescence chemicals with the indolizine core and screen them through a series of in vitro tests utilizing Aß as a target and YI-13 was selected as the final imaging candidate. YI-13 was found to stain and visualize insoluble Aß plaques in the brain tissue, of a transgenic mouse model with five familial AD mutations (5XFAD), by a histochemical approach and to label soluble Aß oligomers within brain lysates of the mouse model under a fluorescence plate reader. Among oligomers aggregated from monomers and synthetic dimers from chemically conjugated monomers, YI-13 preferred the dimeric Aß.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Indolizinas/síntesis química , Indolizinas/farmacología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Fluorescencia , Humanos , Indolizinas/química , Ratones , Ratones Transgénicos , Estructura Molecular , Mutación , Multimerización de Proteína , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología
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