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1.
Sensors (Basel) ; 24(5)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38475113

RESUMO

This paper describes the successes and failures after 4 years of continuous operation of a network of sensors, communicating nodes, and gateways deployed on the Etna Volcano in Sicily since 2019, including a period of Etna intense volcanic activity that occurred in 2021 and resulted in over 60 paroxysms. It documents how the installation of gateways at medium altitude allowed for data collection from sensors up to the summit craters. Most of the sensors left on the volcanic edifice during winters and during this period of intense volcanic activity were destroyed, but the whole gateway infrastructure remained fully operational, allowing for a very fruitful new field campaign two years later, in August 2023. Our experience has shown that the best strategy for IoT deployment on very active and/or high-altitude volcanoes like Etna is to permanently install gateways in areas where they are protected both from meteorological and volcanic hazards, that is mainly at the foot of the volcanic edifice, and to deploy temporary sensors and communicating nodes in the more exposed areas during field trips or in the summer season.

2.
PLoS One ; 18(10): e0292608, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37824461

RESUMO

Mineral springs in Massif Central, France can be characterized by higher levels of natural radioactivity in comparison to the background. The biota in these waters is constantly under radiation exposure mainly from the α-emitters of the natural decay chains, with 226Ra in sediments ranging from 21 Bq/g to 43 Bq/g and 222Rn activity concentrations in water up to 4600 Bq/L. This study couples for the first time micro- and nanodosimetric approaches to radioecology by combining GATE and Geant4-DNA to assess the dose rates and DNA damages to microorganisms living in these naturally radioactive ecosystems. It focuses on unicellular eukaryotic microalgae (diatoms) which display an exceptional abundance of teratological forms in the most radioactive mineral springs in Auvergne. Using spherical geometries for the microorganisms and based on γ-spectrometric analyses, we evaluate the impact of the external exposure to 1000 Bq/L 222Rn dissolved in the water and 30 Bq/g 226Ra in the sediments. Our results show that the external dose rates for diatoms are significant (9.7 µGy/h) and comparable to the threshold (10 µGy/h) for the protection of the ecosystems suggested by the literature. In a first attempt of simulating the radiation induced DNA damage on this species, the rate of DNA Double Strand Breaks per day is estimated to 1.11E-04. Our study confirms the significant mutational pressure from natural radioactivity to which microbial biodiversity has been exposed since Earth origin in hydrothermal springs.


Assuntos
Radioatividade , Rádio (Elemento) , Radônio , Radônio/análise , Método de Monte Carlo , Ecossistema , Radiometria , Água , DNA
3.
Sci Total Environ ; 873: 162270, 2023 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-36801401

RESUMO

Little is still known about the low dose effects of radiation on the microbial communities in the environment. Mineral springs are ecosystems than can be affected by natural radioactivity. These extreme environments are, therefore, observatories for studying the influence of chronic radioactivity on the natural biota. In these ecosystems we find diatoms, unicellular microalgae, playing an essential role in the food chain. The present study aimed to investigate, using DNA metabarcoding, the effect of natural radioactivity in two environmental compartments (i.e. spring sediments and water) on the genetic richness, diversity and structure of diatom communities in 16 mineral springs in the Massif Central, France. Diatom biofilms were collected during October 2019, and a 312 bp region of the chloroplast gene rbcL (coding for the Ribulose Bisphosphate Carboxylase) used as a barcode for taxonomic assignation. A total of 565 amplicon sequence variants (ASV) were found. The dominant ASV were associated with Navicula sanctamargaritae, Gedaniella sp., Planothidium frequentissimum, Navicula veneta, Diploneis vacillans, Amphora copulata, Pinnularia brebissonii, Halamphora coffeaeformis, Gomphonema saprophilum, and Nitzschia vitrea, but some of the ASVs could not be assigned at the species level. Pearson correlation failed to show a correlation between ASV' richness and radioactivity parameters. Non-parametric MANOVA analysis based on ASVs occurrence or abundances revealed that geographical location was the main factor influencing ASVs distribution. Interestingly, 238U was the second factor that explained diatom ASV structure. Among the ASVs in the mineral springs monitored, ASV associated with one of the genetic variants of Planothidium frequentissimum was well represented in the springs and with higher levels of 238U, suggesting its high tolerance to this particular radionuclide. This diatom species may therefore represent a bio-indicator of high natural levels of uranium.


Assuntos
Diatomáceas , Radioatividade , Ecossistema , Diatomáceas/genética , Código de Barras de DNA Taxonômico , Minerais
4.
Sci Rep ; 11(1): 24326, 2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-34934152

RESUMO

We develop a site-bond percolation model, called PERCOVID, in order to describe the time evolution of all epidemics propagating through respiratory tract or by skin contacts in human populations. This model is based on a network of social relationships representing interconnected households experiencing governmental non-pharmaceutical interventions. As a very first testing ground, we apply our model to the understanding of the dynamics of the COVID-19 pandemic in France from December 2019 up to December 2021. Our model shows the impact of lockdowns and curfews, as well as the influence of the progressive vaccination campaign in order to keep COVID-19 pandemic under the percolation threshold. We illustrate the role played by social interactions by comparing two typical scenarios with low or high strengths of social relationships as compared to France during the first wave in March 2020. We investigate finally the role played by the α and δ variants in the evolution of the epidemic in France till autumn 2021, paying particular attention to the essential role played by the vaccination. Our model predicts that the rise of the epidemic observed in July and August 2021 would not result in a new major epidemic wave in France.


Assuntos
COVID-19/epidemiologia , Relações Interpessoais , Modelos Teóricos , COVID-19/prevenção & controle , COVID-19/virologia , França/epidemiologia , Humanos , Pandemias , SARS-CoV-2/isolamento & purificação , Vacinação
5.
Cancers (Basel) ; 13(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34638425

RESUMO

Accurately modeling the radiobiological mechanisms responsible for the induction of DNA damage remains a major scientific challenge, particularly for understanding the effects of low doses of ionizing radiation on living beings, such as the induction of carcinogenesis. A computational approach based on the Monte Carlo technique to simulate track structures in a biological medium is currently the most reliable method for calculating the early effects induced by ionizing radiation on DNA, the primary cellular target of such effects. The Geant4-DNA Monte Carlo toolkit can simulate not only the physical, but also the physico-chemical and chemical stages of water radiolysis. These stages can be combined with simplified geometric models of biological targets, such as DNA, to assess direct and indirect early DNA damage. In this study, DNA damage induced in a human fibroblast cell was evaluated using Geant4-DNA as a function of incident particle type (gammas, protons, and alphas) and energy. The resulting double-strand break yields as a function of linear energy transfer closely reproduced recent experimental data. Other quantities, such as fragment length distribution, scavengeable damage fraction, and time evolution of damage within an analytical repair model also supported the plausibility of predicting DNA damage using Geant4-DNA.The complete simulation chain application "molecularDNA", an example for users of Geant4-DNA, will soon be distributed through Geant4.

6.
Environ Manage ; 67(6): 1137-1144, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33844063

RESUMO

Willows are used as cuttings or in fascines for riverbank soil bioengineering, to control erosion with their high resprouting ability and rapid growth. However, water availability is highly variable along riverbanks both in time and space and constitutes a major stress limiting willow establishment. A species-specific understanding of willow cutting response to water stress is critical to design successful riverbank soil bioengineering projects given exclusive use of local species is often recommended. In a three-month greenhouse experiment, we investigated the effects of three soil moisture treatments (drought-soil saturation-intermittent flooding) on survival, biomass production and root growth of cuttings of three willow species used for soil bioengineering along NE American streams (Salix discolor-S. eriocephala-S. interior). Cutting survival was high for all species and treatments (>89%). Biomass production and root volume only differed between species. S. eriocephala produced the highest biomass and root volume, and S. discolor invested more in belowground than aboveground biomass. Root length responded to soil moisture differently between species. Under intermittent flooding, S. eriocephala produced shorter roots, while S. interior produced longer roots. For riverbank soil bioengineering, S. eriocephala should be favored at medium elevation and S. interior at lower elevation.


Assuntos
Salix , Bioengenharia , Biomassa , Secas , Raízes de Plantas , Solo
7.
Elife ; 92020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33252037

RESUMO

All organisms on Earth are exposed to low doses of natural radioactivity but some habitats are more radioactive than others. Yet, documenting the influence of natural radioactivity on the evolution of biodiversity is challenging. Here, we addressed whether organisms living in naturally more radioactive habitats accumulate more mutations across generations using 14 species of waterlice living in subterranean habitats with contrasted levels of radioactivity. We found that the mitochondrial and nuclear mutation rates across a waterlouse species' genome increased on average by 60% and 30%, respectively, when radioactivity increased by a factor of three. We also found a positive correlation between the level of radioactivity and the probability of G to T (and complementary C to A) mutations, a hallmark of oxidative stress. We conclude that even low doses of natural bedrock radioactivity influence the mutation rate possibly through the accumulation of oxidative damage, in particular in the mitochondrial genome.


Assuntos
Evolução Molecular , Fenômenos Geológicos , Isópodes/genética , Isópodes/efeitos da radiação , Raios Ultravioleta , Animais , Genes Mitocondriais/genética , Mutação , Filogenia
8.
Artigo em Inglês | MEDLINE | ID: mdl-33007976

RESUMO

BACKGROUND: Understanding SARS-CoV-2 dynamics and transmission is a serious issue. Its propagation needs to be modeled and controlled. The Alsace region in the East of France has been among the first French COVID-19 clusters in 2020. METHODS: We confront evidence from three independent and retrospective sources: a population-based survey through internet, an analysis of the medical records from hospital emergency care services, and a review of medical biology laboratory data. We also check the role played in virus propagation by a large religious meeting that gathered over 2000 participants from all over France mid-February in Mulhouse. RESULTS: Our results suggest that SARS-CoV-2 was circulating several weeks before the first officially recognized case in Alsace on 26 February 2020 and the sanitary alert on 3 March 2020. The religious gathering seems to have played a role for secondary dissemination of the epidemic in France, but not in creating the local outbreak. CONCLUSIONS: Our results illustrate how the integration of data coming from multiple sources could help trigger an early alarm in the context of an emerging disease. Good information data systems, able to produce earlier alerts, could have avoided a general lockdown in France.


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Betacoronavirus , COVID-19 , Monitoramento Epidemiológico , França/epidemiologia , Humanos , Comportamento de Massa , Pandemias , Estudos Retrospectivos , SARS-CoV-2
9.
Sensors (Basel) ; 20(10)2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32408560

RESUMO

While radon in soil gases has been identified for decades as a potential precursor of volcanic eruptions, there has been a recent interest for monitoring radon in air on active volcanoes. We present here the first network of outdoor air radon sensors that was installed successfully on Mt. Etna volcano, Sicily, Italy in September 2019. Small radon sensors designed for workers and home dosimetry were tropicalized in order to be operated continuously in harsh volcanic conditions with an autonomy of several months. Two stations have been installed on the south flank of the volcano at ~3000 m of elevation. A private network has been deployed in order to transfer the measurements from the stations directly to a server located in France, using a low-power wide-area transmission technology from Internet of Things (IoT) called LoRaWAN. Data finally feed a data lake, allowing flexibility in data management and sharing. A first analysis of the radon datasets confirms previous observations, while adding temporal information never accessed before. The observed performances confirm IoT solutions are very adapted to active volcano monitoring in terms of range, autonomy, and data loss.

10.
Sci Rep ; 9(1): 14891, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31624294

RESUMO

Over millennia, life has been exposed to ionizing radiation from cosmic rays and natural radioisotopes. Biological experiments in underground laboratories have recently demonstrated that the contemporary terrestrial radiation background impacts the physiology of living organisms, yet the evolutionary consequences of this biological stress have not been investigated. Explaining the mechanisms that give rise to the results of underground biological experiments remains difficult, and it has been speculated that hereditary mechanisms may be involved. Here, we have used evolution experiments in standard and very low-radiation backgrounds to demonstrate that environmental ionizing radiation does not significantly impact the evolutionary trajectories of E. coli bacterial populations in a 500 generations evolution experiment.


Assuntos
Radiação de Fundo/efeitos adversos , Escherichia coli/genética , Escherichia coli/efeitos da radiação , Evolução Molecular , Radiação Cósmica/efeitos adversos , Relação Dose-Resposta à Radiação , Escherichia coli/crescimento & desenvolvimento , Aptidão Genética/efeitos da radiação , Mutação
11.
Phys Med ; 62: 152-157, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31109825

RESUMO

The advancement of multidisciplinary research fields dealing with ionising radiation induced biological damage - radiobiology, radiation physics, radiation protection and, in particular, medical physics - requires a clear mechanistic understanding of how cellular damage is induced by ionising radiation. Monte Carlo (MC) simulations provide a promising approach for the mechanistic simulation of radiation transport and radiation chemistry, towards the in silico simulation of early biological damage. We have recently developed a fully integrated MC simulation that calculates early single strand breaks (SSBs) and double strand breaks (DSBs) in a fractal chromatin based human cell nucleus model. The results of this simulation are almost equivalent to past MC simulations when considering direct/indirect strand break fraction, DSB yields and fragment distribution. The simulation results agree with experimental data on DSB yields within 13.6% on average and fragment distributions agree within an average of 34.8%.


Assuntos
Núcleo Celular/genética , Núcleo Celular/efeitos da radiação , Dano ao DNA , Fractais , Modelos Biológicos , Método de Monte Carlo , Animais , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Quebras de DNA de Cadeia Simples/efeitos da radiação , Fatores de Tempo
12.
J Environ Manage ; 231: 1-9, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30326333

RESUMO

Competitive interactions seem to play a major role in invasive plant success. However, they have mostly been addressed through the invader impacts on other species of the plant community and rarely through the way plant communities can contain alien species. Understanding such mechanisms would help in designing restoration projects using plant community competitive properties to control invasive populations. In this study, we looked at the role of competitive interactions in the success of Fallopia japonica (Houtt.) Ronse Decraene using a native willow frequently used in bioengineering techniques: Salix viminalis L. S. viminalis has a high growth rate and is, as such, a potential candidate to compete with F. japonica in restoration projects of invaded areas. Both species were grown in semi-controlled conditions in mesocosms (truck dumpsters), alone or in competition. Morphological traits (plant height, specific leaf area) as well as biomass (aboveground and underground) were measured on each species during two growing seasons. We also quantified spatial expansion of F. japonica. Even under a dense canopy of S. viminalis, F. japonica was able to survive and grow. However, its performance was significantly reduced compared to monocultures and its spatial colonization was less extended. Although S. viminalis biomass was affected by F. japonica, F. japonica expressed competitive stress through a modification of ramet density and height. There was no significant effect of F. japonica on S. viminalis height, enabling this species to dominate. Synthesis and applications: We conclude that S. viminalis succeeded in reducing F. japonica growth by developing a competitive canopy. Bioengineering techniques aiming at restoring a competitive neighborhood can control F. japonica. However, F. japonica's broad underground extension should be taken into account in any management strategy in order to successfully limit its development and spatial spread.


Assuntos
Fallopia japonica , Polygonum , Salix , Biomassa , Folhas de Planta
13.
Int J Mol Sci ; 19(10)2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30304836

RESUMO

Dinitroanilines are chemical compounds with high selectivity for plant cell α-tubulin in which they promote microtubule depolymerization. They target α-tubulin regions that have diverged over evolution and show no effect on non-photosynthetic eukaryotes. Hence, they have been used as herbicides over decades. Interestingly, dinitroanilines proved active on microtubules of eukaryotes deriving from photosynthetic ancestors such as Toxoplasma gondii and Plasmodium falciparum, which are responsible for toxoplasmosis and malaria, respectively. By combining differential in silico screening of virtual chemical libraries on Arabidopsis thaliana and mammal tubulin structural models together with cell-based screening of chemical libraries, we have identified dinitroaniline related and non-related compounds. They inhibit plant, but not mammalian tubulin assembly in vitro, and accordingly arrest A. thaliana development. In addition, these compounds exhibit a moderate cytotoxic activity towards T. gondii and P. falciparum. These results highlight the potential of novel herbicidal scaffolds in the design of urgently needed anti-parasitic drugs.


Assuntos
Apicomplexa/fisiologia , Plantas/metabolismo , Plantas/parasitologia , Tubulina (Proteína)/metabolismo , Animais , Células HeLa , Humanos , Microtúbulos/metabolismo , Modelos Moleculares , Fotossíntese , Células Vegetais/metabolismo , Plasmodium falciparum , Conformação Proteica , Tubulina (Proteína)/química , Tubulina (Proteína)/genética
14.
Phys Med ; 48: 135-145, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29628360

RESUMO

Mechanistic modelling of DNA damage in Monte Carlo simulations is highly sensitive to the parameters that define DNA damage. In this work, we use a simple testing geometry to investigate how different choices of physics models and damage model parameters can change the estimation of DNA damage in a mechanistic DNA damage simulation built in Geant4-DNA. The choice of physics model can lead to variations by up to a factor of two in the yield of physically induced strand breaks, and the parameters that determine scavenging, and physical and chemical single strand break induction can have even larger consequences. Using low energy electrons as primary particles, a variety of parameters are tested in this geometry in order to arrive at a parameter set consistent with past simulation studies. We find that the modelling of scavenging can play an important role in determining results, and speculate that high-scavenging regimes, where only chemical radicals within 1 nm of DNA are simulated, could provide a good means of testing mechanistic DNA simulations.


Assuntos
Dano ao DNA , Método de Monte Carlo , DNA/química , DNA/genética , Elétrons/efeitos adversos , Modelos Moleculares , Conformação de Ácido Nucleico
15.
Phys Med ; 48: 146-155, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29371062

RESUMO

We extended a generic Geant4 application for mechanistic DNA damage simulations to an Escherichia coli cell geometry, finding electron damage yields and proton damage yields largely in line with experimental results. Depending on the simulation of radical scavenging, electrons double strand breaks (DSBs) yields range from 0.004 to 0.010 DSB Gy-1 Mbp-1, while protons have yields ranging from 0.004 DSB Gy-1 Mbp-1 at low LETs and with strict assumptions concerning scavenging, up to 0.020 DSB Gy-1 Mbp-1 at high LETs and when scavenging is weakest. Mechanistic DNA damage simulations can provide important limits on the extent to which physical processes can impact biology in low background experiments. We demonstrate the utility of these studies for low dose radiation biology calculating that in E. coli, the median rate at which the radiation background induces double strand breaks is 2.8 × 10-8 DSB day-1, significantly less than the mutation rate per generation measured in E. coli, which is on the order of 10-3.


Assuntos
Dano ao DNA , Elétrons/efeitos adversos , Escherichia coli/genética , Escherichia coli/efeitos da radiação , Método de Monte Carlo , Prótons/efeitos adversos , DNA Bacteriano/química , DNA Bacteriano/genética , Escherichia coli/citologia , Modelos Moleculares , Conformação de Ácido Nucleico
16.
Evol Appl ; 10(7): 658-666, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28717386

RESUMO

Biological experiments conducted in underground laboratories over the last decade have shown that life can respond to relatively small changes in the radiation background in unconventional ways. Rapid changes in cell growth, indicative of hormetic behaviour and long-term inheritable changes in antioxidant regulation have been observed in response to changes in the radiation background that should be almost undetectable to cells. Here, we summarize the recent body of underground experiments conducted to date, and outline potential mechanisms (such as cell signalling, DNA repair and antioxidant regulation) that could mediate the response of cells to low radiation backgrounds. We highlight how multigenerational studies drawing on methods well established in studying evolutionary biology are well suited for elucidating these mechanisms, especially given these changes may be mediated by epigenetic pathways. Controlled evolution experiments with model organisms, conducted in underground laboratories, can highlight the short- and long-term differences in how extremely low-dose radiation environments affect living systems, shining light on the extent to which epimutations caused by the radiation background propagate through the population. Such studies can provide a baseline for understanding the evolutionary responses of microorganisms to ionizing radiation, and provide clues for understanding the higher radiation environments around uranium mines and nuclear disaster zones, as well as those inside nuclear reactors.

17.
PLoS One ; 11(11): e0166364, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27851794

RESUMO

At very low radiation dose rates, the effects of energy depositions in cells by ionizing radiation is best understood stochastically, as ionizing particles deposit energy along tracks separated by distances often much larger than the size of cells. We present a thorough analysis of the stochastic impact of the natural radiative background on cells, focusing our attention on E. coli grown as part of a long term evolution experiment in both underground and surface laboratories. The chance per day that a particle track interacts with a cell in the surface laboratory was found to be 6 × 10-5 day-1, 100 times less than the expected daily mutation rate for E. coli under our experimental conditions. In order for the chance cells are hit to approach the mutation rate, a gamma background dose rate of 20 µGy hr-1 is predicted to be required.


Assuntos
Radiação de Fundo , Simulação por Computador , Escherichia coli/efeitos da radiação , Radiação Ionizante , Relação Dose-Resposta à Radiação , Elétrons , Funções Verossimilhança
18.
J Environ Manage ; 151: 65-75, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25532058

RESUMO

Erosion control is a major issue in the Prealps region since piedmont is subject to both intense flood hazards and anthropic pressure. Riverbank protections may have major impacts on local ecosystem functioning and ecological corridor continuity. This study aimed to estimate the effects of the types of riverbank protection technique (from pure riprap to pure bioengineering) on the taxonomic and ecological composition of plant communities in comparison with unmanaged riverbanks as the referential system. Thirty-eight embankments were sampled in the foothills of the French and Swiss Alps. Four distinct riverbank techniques were analyzed and natural young willow stands were chosen as the referential system. At each site, vegetation was sampled along three transects from the waterline to the top of the riverbank. Plant communities were characterized using biological group composition (growth forms and life history, life strategies and distribution in space and time) and functional diversity indices (MFAD, FDc and wFDc). We identified 177 distinct plant species on 38 sites. Higher species richness levels were observed on bioengineered banks (from an average of 12 species recorded on ripraps to 27 species recorded on bioengineered banks) strongly dominated by Salicaceae species, especially for fascine and cribwall banks. Functional analyses of plant communities highlighted significant differences among bank types (p-value: 0.001) for all selected biological groups. Competitive - ruderal strategy, rooting shoots, stems or leaves that lie down or break off, and unisexual - dioecious, as well as pioneer plants and low shrubs (<4 m tall) distinguished bioengineered bank types. Functional diversity indices confirmed these differences among bank types (MFAD: p-value: 0.002; FDc: p-value: 0.003; wFDc: p-value: 0.005). Riprap always showed the lowest levels on functional diversity indices, fascine and cribwall banks were at the medium level and finally mixed and natural banks the highest level. These results confirm the low ecological potential of purely hard engineering techniques and highlight the similarity of bioengineered techniques and unmanaged riverbanks.


Assuntos
Conservação dos Recursos Naturais/métodos , Ecossistema , Plantas/classificação , Rios , Biodiversidade , Bioengenharia/métodos , Monitoramento Ambiental , França , Humanos , Suíça
19.
Biotechnol Lett ; 33(11): 2185-91, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21735260

RESUMO

Human intestinal maltase (HMA) is an α-glucosidase that hydrolyses α-1,4-linkages from the non-reducing end of malto-oligosaccharides. HMA is an important target to discover of new drugs for the treatment of type 2 diabetes. In this study, 308,307 compounds were virtually screened with HMA using Autodock 3.0.5 in a WISDOM production environment to discover novel inhibitors. The 42 top-scoring free binding energy compounds, representing 17 groups containing potential hydrogen bonding with key residues in the active site pocket of HMA, were tested in vitro for their inhibitory activities against recombinant HMA expressed from Pichia pastoris. Compounds 17 and 18 were competitive inhibitors exclusively for HMA without any in vitro inhibition for human pancreatic α-amylase. The K(i) values were 20 µM for both compound 17 and 18.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/metabolismo , Inibidores de Glicosídeo Hidrolases , Inibidores Enzimáticos/química , Humanos , Cinética , Simulação de Dinâmica Molecular , Estrutura Molecular , Pichia/efeitos dos fármacos , Pichia/genética
20.
Bioorg Med Chem Lett ; 21(10): 3088-91, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21470860

RESUMO

The 3C-like protease (3CL(pro)) of severe acute respiratory syndrome associated coronavirus (SARS-CoV) is vital for SARS-CoV replication and is a promising drug target. Structure based virtual screening of 308307 chemical compounds was performed using the computation tool Autodock 3.0.5 on a WISDOM Production Environment. The top 1468 ranked compounds with free binding energy ranging from -14.0 to -17.09 kcal mol(-1) were selected to check the hydrogen bond interaction with amino acid residues in the active site of 3CL(pro). Fifty-three compounds from 35 main groups were tested in an in vitro assay for inhibition of 3CL(pro) expressed by Escherichia coli. Seven of the 53 compounds were selected; their IC(50) ranged from 38.57±2.41 to 101.38±3.27 µM. Two strong 3CL(pro) inhibitors were further identified as competitive inhibitors of 3CL(pro) with K(i) values of 9.11±1.6 and 9.93±0.44 µM. Hydrophobic and hydrogen bond interactions of compound with amino acid residues in the active site of 3CL(pro) were also identified.


Assuntos
Simulação por Computador , Sistemas de Liberação de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores de Proteases , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas , Proteínas Virais/antagonistas & inibidores , Proteases Virais 3C , Ligação Competitiva , Cisteína Endopeptidases/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/enzimologia , Proteínas Virais/genética
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