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ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter related to the clinical multidrug resistance (MDR) phenomenon. Identifying ABCG2 inhibitors could help discover extraordinary curative strategies for carcinoma remediation. Hitherto, there is no medication drug inhibiting ABCG2 transporter, notwithstanding that a considerable number of drugs have been submitted to clinical-trial and investigational phases. In the search for unprecedented chemical compounds that could inhibit the ABCG2 transporter, an in silico screening was conducted on the Naturally Occurring Plant-based Anticancer Compound-Activity-Target (NPACT) database containing 1574 compounds. Inhibitor-ABCG2 binding affinities were estimated based on molecular docking and molecular minimization (MM) calculations and compared to a co-crystallized inhibitor (BWQ) acting as a reference inhibitor. Molecular dynamics (MD) simulations pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations were further executed for compounds with MM-GBSA//MM binding energies lower than BWQ (calc. - 60.5 kcal/mol). NPACT00968 and NPACT01545 demonstrated auspicious inhibitory activities according to binding affinities (ΔGbinding) over the 100 ns MD simulations that were nearly one and a half folds compared to BWQ (- 100.4, - 94.7, and - 62.9 kcal/mol, respectively). Throughout the 100 ns MD simulations, structural and energetical analyses unveiled outstanding stability of the ABCG2 transporter when bound with NPACT00968 and NPACT01545. In silico calculations hold a promise for those two inhibitors as drug candidates of ABCG2 transporter and emphasize that further in vitro and in vivo experiments are guaranteed.
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Antineoplásicos , Resistencia a Medicamentos Antineoplásicos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Simulação de Acoplamento Molecular , Estudos Prospectivos , Antineoplásicos/química , Descoberta de DrogasRESUMO
Over the past decade, many databases focusing on microsatellite mining on a genomic scale were released online with at least one of the following major deficiencies: (i) lacking the classification of microsatellites as genic or non-genic, (ii) not comparing microsatellite motifs at both genic and non-genic levels in order to identify unique motifs for each class or (iii) missing SSR marker development. In this study, we have developed 'SSRome' as a web-based, user-friendly, comprehensive and dynamic database with pipelines for exploring microsatellites in 6533 organisms. In the SSRome database, 158 million microsatellite motifs are identified across all taxa, in addition to all the mitochondrial and chloroplast genomes and expressed sequence tags available from NCBI. Moreover, 45.1 million microsatellite markers were developed and classified as genic or non-genic. All the stored motif and marker datasets can be downloaded freely. In addition, SSRome provides three user-friendly tools to identify, classify and compare motifs on either a genome- or transcriptome-wide scale. With the implementation of PHP, HTML and JavaScript, users can upload their data for analysis via a user-friendly GUI. SSRome represents a powerful database and mega-tool that will assist researchers in developing and dissecting microsatellite markers on a high-throughput scale.
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Biologia Computacional/métodos , Bases de Dados Genéticas , Marcadores Genéticos , Genômica/métodos , Repetições de Microssatélites , Design de Software , Interface Usuário-Computador , Navegador , Fluxo de TrabalhoRESUMO
The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ΔGbinding < -33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ΔGbinding values of -43.8 and -34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.
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Antozoários/química , Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus/antagonistas & inibidores , Inibidores de Protease de Coronavírus/farmacologia , Diterpenos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , COVID-19/virologia , Proteases 3C de Coronavírus/metabolismo , Inibidores de Protease de Coronavírus/química , Inibidores de Protease de Coronavírus/isolamento & purificação , Diterpenos/química , Diterpenos/isolamento & purificação , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , SARS-CoV-2/enzimologia , SARS-CoV-2/patogenicidade , Relação Estrutura-AtividadeRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for the COVID-19 pandemic, which generated more than 1.82 million deaths in 2020 alone, in addition to 83.8 million infections. Currently, there is no antiviral medication to treat COVID-19. In the search for drug leads, marine-derived metabolites are reported here as prospective SARS-CoV-2 inhibitors. Two hundred and twenty-seven terpene natural products isolated from the biodiverse Red-Sea ecosystem were screened for inhibitor activity against the SARS-CoV-2 main protease (Mpro) using molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area binding energy calculations. On the basis of in silico analyses, six terpenes demonstrated high potency as Mpro inhibitors with ΔGbinding ≤ -40.0 kcal/mol. The stability and binding affinity of the most potent metabolite, erylosides B, were compared to the human immunodeficiency virus protease inhibitor, lopinavir. Erylosides B showed greater binding affinity towards SARS-CoV-2 Mpro than lopinavir over 100 ns with ΔGbinding values of -51.9 vs. -33.6 kcal/mol, respectively. Protein-protein interactions indicate that erylosides B biochemical signaling shares gene components that mediate severe acute respiratory syndrome diseases, including the cytokine- and immune-signaling components BCL2L1, IL2, and PRKC. Pathway enrichment analysis and Boolean network modeling were performed towards a deep dissection and mining of the erylosides B target-function interactions. The current study identifies erylosides B as a promising anti-COVID-19 drug lead that warrants further in vitro and in vivo testing.
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Invertebrados/química , SARS-CoV-2/metabolismo , Terpenos/química , Proteínas da Matriz Viral/antagonistas & inibidores , Animais , Sítios de Ligação , COVID-19/virologia , Humanos , Ligação de Hidrogênio , Invertebrados/metabolismo , Lopinavir/química , Lopinavir/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteases/química , Inibidores de Proteases/isolamento & purificação , Inibidores de Proteases/uso terapêutico , Ligação Proteica , SARS-CoV-2/isolamento & purificação , Terpenos/isolamento & purificação , Terpenos/metabolismo , Terpenos/uso terapêutico , Termodinâmica , Proteínas da Matriz Viral/metabolismo , Tratamento Farmacológico da COVID-19RESUMO
Plant biostimulants (PBs) are used globally to increase crop yield and productivity. PBs such as (Serendipita indica) or algal extracts stimulate and accelerate plant physiological processes. The physiological, ecological, and biochemical effects of (Serendipita indica) or algal extracts individually and in combination on basil plant (Ocimum basilicum L.) were investigated. Macroalgae samples were collected from Abu Qir, Alexandria, Egypt. The growth parameters, chlorophyll index, and biochemical composition of basil were analyzed at 90th day. The (Chlorella vulgaris) + (Serendipita indica) (MI + F) treatment increased chlorophyll index by 61.7% (SPAD) compared to control. (Chlorella vulgaris) had the highest growth hormones, including GA3 at 158.2 ppb, GA4 at 149.1 ppb, GA7 at 142.6 ppb, IAA at 136.6 ppb, and TC at 130.9 ppb, while (Ulva lactuca) had the lowest. The MI + F treatment yielded the highest essential oil and antioxidant values. Treatment with (Chlorella vulgaris) increased S. indica colonization by 66%. In contrast, Ulva lactuca and (Padina Pavonica) inhibited S. indica colonization by 80% and 40%, respectively. (Ulva lactuca) and (Padina Pavonica) inhibited S. indica colonization by 80% and 40%, respectively. Combined treatments had a greater influence on basil performance than the individual treatments. The evidence of synergistic/additive benefits to plants performance due to the interactive effects of (Chlorella vulgaris) and (Serendipita indica) had been studied. Complementary modes of action between (Chlorella vulgaris) and (Serendipita indica), through their components newly emerging properties on basil, may explain observed synergistic effects. This study explores the potential of microbial-algal interactions, particularly (Chlorella vulgaris) and (Serendipita indica), as innovative plant biostimulants. These interactions demonstrate positive effects on basil growth, offering promise for more effective microbial-based formulations to enhance crop productivity and sustainability in agriculture. These novelties will help create a second generation of PBs with integrated and complementary actions.
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Basidiomycota , Chlorella vulgaris , Algas Comestíveis , Ocimum basilicum , Ocimum , Ulva , ClorofilaRESUMO
The failure of chemotherapy in the treatment of carcinoma is mainly due to the development of multidrug resistance (MDR), which is largely caused by the overexpression of P-glycoprotein (P-gp/ABCB1/MDR1). Until recently, the 3D structure of the P-gp transporter has not been experimentally resolved, which restricted the discovery of prospective P-gp inhibitors utilizing in silico techniques. In this study, the binding energies of 512 drug candidates in clinical or investigational stages were assessed as potential P-gp inhibitors employing in silico methods. On the basis of the available experimental data, the performance of the AutoDock4.2.6 software to predict the drug-P-gp binding mode was initially validated. Molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics-generalized Born surface area (MM-GBSA) binding energy computations were subsequently conducted to screen the investigated drug candidates. Based on the current results, five promising drug candidates, namely valspodar, dactinomycin, elbasvir, temsirolimus, and sirolimus, showed promising binding energies against P-gp transporter with ΔGbinding values of -126.7, -112.1, -111.9, -102.9, and -101.4 kcal/mol, respectively. The post-MD analyses revealed the energetical and structural stabilities of the identified drug candidates in complex with the P-gp transporter. Furthermore, in order to mimic the physiological conditions, the potent drugs complexed with the P-gp were subjected to 100 ns MD simulations in an explicit membrane-water environment. The pharmacokinetic properties of the identified drugs were predicted and demonstrated good ADMET characteristics. Overall, these results indicated that valspodar, dactinomycin, elbasvir, temsirolimus, and sirolimus hold promise as prospective P-gp inhibitors and warrant further invitro/invivo investigations.
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Resistência a Múltiplos Medicamentos , Neoplasias , Humanos , Simulação de Acoplamento Molecular , Dactinomicina/uso terapêutico , Estudos Prospectivos , Neoplasias/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/uso terapêutico , Sirolimo , Descoberta de Drogas , Resistencia a Medicamentos AntineoplásicosRESUMO
The structure and dynamic of soil bacterial community play a crucial role in soil health and plant productivity. However, there is a gap in studying the un-/or reclaimed soil bacteriome and its impact on future plant performance. The 16S metagenomic analysis is expensive and utilize sophisticated pipelines, making it unfavorable for researchers. Here, we aim to perform (1) in silico and in vitro validation of taxon-specific qPCR primer-panel in the detection of the beneficial soil bacterial community, to ensure its specificity and precision, and (2) multidimensional analysis of three soils/locations in Egypt ('Q', 'B', and 'G' soils) in terms of their physicochemical properties, bacteriome composition, and wheat productivity as a model crop. The in silico results disclosed that almost all tested primers showed high specificity and precision toward the target taxa. Among 17 measured soil properties, the electrical conductivity (EC) value (up to 5 dS/m) of 'Q' soil provided an efficient indicator for soil health among the tested soils. The 16S NGS analysis showed that the soil bacteriome significantly drives future plant performance, especially the abundance of Proteobacteria and Actinobacteria as key indicators. The functional prediction analysis results disclosed a high percentage of N-fixing bacterial taxa in 'Q' soil compared to other soils, which reflects their positive impact on wheat productivity. The taxon-specific qPCR primer-panel results revealed a precise quantification of the targeted taxa compared to the 16S NGS analysis. Moreover, 12 agro-morphological parameters were determined for grown wheat plants, and their results showed a high yield in the 'Q' soil compared to other soils; this could be attributed to the increased abundance of Proteobacteria and Actinobacteria, high enrichment in nutrients (N and K), or increased EC/nutrient availability. Ultimately, the potential use of a taxon-specific qPCR primer-panel as an alternative approach to NGS provides a cheaper, user-friendly setup with high accuracy.
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The present investigation aims to highlight the role of salt priming in mitigating salt stress on faba bean. In the absence of priming, the results reflected an increase in H2O2 generation and lipid peroxidation in plants subjected to 200 mM salt shock for one week, accompanied by a decline in growth, photosynthetic pigments, and yield. As a defense, the shocked plants showed enhancements in ascorbate peroxidase (APX), catalase (CAT), glutathione reductase (GR), peroxidase (POX), and superoxide dismutase (SOD) activities. Additionally, the salt shock plants revealed a significant increase in phenolics and proline content, as well as an increase in the expression levels of glutathione (GSH) metabolism-related genes (the L-ascorbate peroxidase (L-APX) gene, the spermidine synthase (SPS) gene, the leucyl aminopeptidase (LAP) gene, the aminopeptidase N (AP-N) gene, and the ribonucleo-side-diphosphate reductase subunit M1 (RDS-M) gene). On the other hand, priming with increasing concentrations of NaCl (50-150 mM) exhibited little significant reduction in some growth- and yield-related traits. However, it maintained a permanent alert of plant defense that enhanced the expression of GSH-related genes, proline accumulation, and antioxidant enzymes, establishing a solid defensive front line ameliorating osmotic and oxidative consequences of salt shock and its injurious effect on growth and yield.
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The Red Sea soft coral Sarcophyton acutum ethyl acetate extract has afforded one new cembranoid; sarcacutumolid A (1), along with six known metabolites have been isolated from S. acutum for the first time (2-7). Chemical structures were elucidated by employing several spectroscopic analyses. The cytotoxic potential of the isolated compounds was assessed against four human cancer cell lines; hepatocellular (HepG2), cervical (HeLa), breast (MCF-7) and colorectal cancer (Colo-205). Sarcacutumolid A (1) and gorgosterol (7) inhibited colorectal cancer cell proliferation in a concentration-dependent manner with IC50 values of 35.5 and 44.0 µM, respectively.
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ABCG2 is a substantial member of the ABC transporter superfamily that plays a significant role in multidrug resistance in cancer. Until recently, the 3D structure of ABCG2 has not been resolved, which resulted in the limitation of developing potential ABCG2 inhibitors using structure-based drug discovery. Herein, eMolecules, ChEMBL, and ChEBI databases, containing >25 million compounds, were virtually screened against the ABCG2 transporter in homodimer form. Performance of AutoDock4.2.6 software to predict inhibitor-ABCG2 binding mode and affinity were validated on the basis of available experimental data. The explored databases were filtered based on docking scores. The most potent hits with binding affinities higher than that of experimental bound ligand (MZ29) were then selected and subjected to molecular mechanics minimization, followed by binding energy calculation using molecular mechanics-generalized Born surface area (MM-GBSA) approach. Furthermore, molecular dynamics simulations for 50â ns, followed by MM-GBSA binding energy calculations, were performed for the promising compounds, unveiling eight potential inhibitors with binding affinities <-55.8â kcal/mol. Structural and energetic analyses demonstrated the stability of the eight identified inhibitors over the 50â ns MD simulation. This research sheds light on the potentiality of the identified ABCG2 inhibitors as a therapeutic approach to overcome multidrug resistance cancer therapy.
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Neoplasias da Mama , Simulação de Dinâmica Molecular , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Detecção Precoce de Câncer , Feminino , Humanos , Ligantes , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/metabolismoRESUMO
This work aimed to evaluate the anti-androgenic activity of S. blackburniana Glazebrook, S. causiarum (O. F. Cook) Becc, and S. palmetto (Walter) Lodd. Ex Schult fruit extracts in rats using Hershberger assay. Furthermore, to annotate secondary metabolites using LC-HRMS technique, to investigate underlying mechanisms responsible for 5-α-reductase inhibitory activity in silico and to compare cytotoxic effects in vitro against human prostatic stromal myofibroblast (WPMY-1) and human benign prostatic hyperplasia (BPH-1) cell lines using MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (spectrophotometrically). The results showed significant anti-androgenic implications with varying degrees, markedly decreased sex organ weights, reduction in testosterone and increase in LH and FSH serum levels. Genetic diversity study ensured the correct genotype and revealed outperformance of SCoT compared with CBDP markers to interpret polymorphism among selected species. S. blackburniana exhibited selective cytotoxic activity against BPH-1 compared to finasteride. Molecular docking of 59 dereplicated metabolites belonging to various chemical classes revealed that helasaoussazine, pinoresinol and tetra-O-caffeoylquinic acid are the top inhibitors of 5-α-reductase-2. Our study provides an insight into the anti-androgenic activity of selected species of Egyptian Sabal supported by docking study for the first time, demonstrates safety toward liver and kidney and highlights a new potential therapeutic candidate for anti-androgenic related disease such as benign prostatic hyperplasia.
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Hiperplasia Prostática , Serenoa , Antagonistas de Androgênios/farmacologia , Animais , Egito , Frutas , Humanos , Masculino , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/genética , RatosRESUMO
Frequent applications of synthetic insecticides might cause environmental pollution due to the high residue. In addition, increasing insecticide resistance in many insect pests requires novel pest control methods. Nanotechnology could be a promising field of modern agriculture, and is receiving considerable attention in the development of novel nano-agrochemicals, such as nanoinsectticides and nanofertilizers. This study assessed the effects of the lethal and sublethal concentrations of chlorantraniliprole, thiocyclam, and their nano-forms on the development, reproductive activity, oxidative stress enzyme activity, and DNA changes in the black cutworm, Agrotis ipsilon, at the molecular level. The results revealed that A. ipsilon larvae were more susceptible to the nano-forms than the regular forms of both nano chlorine and sulfur within the chlorantraniliprole and thiocyclam insecticides, respectively, with higher toxicities than the regular forms (ca. 3.86, and ca.2.06-fold, respectively). Significant differences in biological parameters, including developmental time and reproductive activity (fecundity and hatchability percent) were also observed. Correspondingly, increases in oxidative stress enzyme activities were observed, as were mutagenic effects on the genomic DNA of A. ipsilon after application of the LC50 of the nano-forms of both insecticides compared to the control. These promising results could represent a crucial step toward developing efficient nanoinsecticides for sustainable control of A. ipsilon.
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Lepidópteros , AnimaisRESUMO
The main protease (Mpro) is a potential druggable target in SARS-CoV-2 replication. Herein, an in silico study was conducted to mine for Mpro inhibitors from toxin sources. A toxin and toxin-target database (T3DB) was virtually screened for inhibitor activity towards the Mpro enzyme utilizing molecular docking calculations. Promising toxins were subsequently characterized using a combination of molecular dynamics (MD) simulations and molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. According to the MM-GBSA binding energies over 200 ns MD simulations, three toxins-namely philanthotoxin (T3D2489), azaspiracid (T3D2672), and taziprinone (T3D2378)-demonstrated higher binding affinities against SARS-CoV-2 Mpro than the co-crystalized inhibitor XF7 with MM-GBSA binding energies of -58.9, -55.9, -50.1, and -43.7 kcal/mol, respectively. The molecular network analyses showed that philanthotoxin provides a ligand lead using the STRING database, which includes the biochemical top 20 signaling genes CTSB, CTSL, and CTSK. Ultimately, pathway enrichment analysis (PEA) and Reactome mining results revealed that philanthotoxin could prevent severe lung injury in COVID-19 patients through the remodeling of interleukins (IL-4 and IL-13) and the matrix metalloproteinases (MMPs). These findings have identified that philanthotoxin-a venom of the Egyptian solitary wasp-holds promise as a potential Mpro inhibitor and warrants further in vitro/in vivo validation.
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BACKGROUND: In the pharmaceutical sector, tissue culture techniques for large-scale production of natural chemicals can be a less expensive alternative to large-scale synthesis. Although recent biotransformation research have used plant cell cultures to target a wide range of bioactive compounds, more compiled information and synopses are needed to better understand metabolic pathways and improve biotransformation efficiencies. PURPOSE: This report reviews the biochemical transformation of phenolic natural products by plant cell cultures in order to identify potential novel biotechnological approaches for ensuring more homogeneous and stable phenolic production year-round under controlled environmental conditions. METHODS: Articles on the use of plant cell culture for polyphenolic and flavonoid transformations (1988 - 2021) were retrieved from SciFinder, PubMed, Scopus, and Web of Science through electronic and manual search in English. Following that, the authors chose the required papers based on the criteria they defined. The following keywords were used for the online search: biotransformation, Plant cell cultures, flavonoids, phenolics, and pharmaceutical products. RESULTS: The initial search found a total of 96 articles. However, only 70 of them were selected as they met the inclusion criteria defined by the authors. The analysis of these studies revealed that plant tissue culture is applicable for the large-scale production of plant secondary metabolites including the phenolics, which have high therapeutic value. CONCLUSION: Plant tissue cultures could be employed as an efficient technique for producing secondary metabolites including phenolics. Phenolics possess a wide range of therapeutic benefits, as anti-oxidant, anti-cancer, and anti-inflammatory properties. Callus culture, suspension cultures, transformation, and other procedures have been used to improve the synthesis of phenolics. Their production on a large scale is now achievable. More breakthroughs will lead to newer insights and, without a doubt, to a new era of phenolics-based pharmacological agents for the treatment of a variety of infectious and degenerative disorders.
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Flavonoides , Fenóis , Antioxidantes/metabolismo , Técnicas de Cultura de Células , Flavonoides/análise , Fenóis/análise , Plantas/metabolismoRESUMO
ABSTRACT: Over the past decade, the problem of finding an efficient gene-targeting marker set or signature for plant trait characterization has remained challenging. Many databases focusing on pathway mining have been released with one major deficiency, as they lack to develop marker sets that target only genes controlling a specific pathway or certain biological process. Herein, we present the PlantPathMarks database (PPMdb) as a comprehensive, web-based, user-friendly, and interactive hub for pathway-based markers in plant genomes. Based on our newly developed pathway gene set mining approach, two novel pathway-based marker systems called pathway gene-targeted markers (PGTMs) and pathway microsatellite-targeted markers (PMTMs) were developed as a novel class of annotation-based markers. In the PPMdb database, 2,690,742 pathway-based markers reflecting 9,894 marker panels were developed across 82 plant genomes. The markers include 691,555 PGTMs and 1,999,187 PMTMs. Across these genomes, 165,378 enzyme-coding genes were mapped against 126 KEGG reference pathway maps. PPMdb is furnished with three interactive visualization tools (Map Browse, JBrowse and Species Comparison) to visualize, map, and compare the developed markers over their KEGG reference pathway maps. All the stored marker panels can be freely downloaded. PPMdb promises to create a radical shift in the paradigm of the area of molecular marker research. The use of PPMdb as a mega-tool represents an impediment for non-bioinformatician plant scientists and breeders. PPMdb is freely available at http://ppmdb.easyomics.org .
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Bases de Dados Genéticas , Genes de Plantas , Marcadores Genéticos/genética , Plantas/genéticaRESUMO
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the greatest cause of cancer-related death in the world. Garden cress (Lepidium sativum) seeds have been proven to possess extraordinary antioxidant, anti-inflammatory, hypothermic, and analgesic properties. In this study, in vitro cytotoxic efficiency evaluation of L. sativum fractions was performed against two hepatocellular carcinoma cell lines (HuH-7 and HEPG-2), and the expression of some apoptotic genes was explored. In addition, the chemical composition of a potent extract of L. sativum was analyzed using gas chromatography coupled with mass spectrometry. Then, molecular docking analysis was implemented to identify the potential targets of the L. sativum components' most potent extract. Overall, the n-hexane extract was the most potent against the two HCC cell lines. Moreover, these cytotoxicity levels were supported by the significant downregulation of EGFR and BCL2 gene expression levels and the upregulation of SMAD3, BAX, and P53 expression levels in both HuH-7 and HEPG2 cell lines. Regarding L. sativum's chemical composition, GC-MS analysis of the n-hexane extract led to the identification of thirty compounds, including, mainly, hydrocarbons and terpenoids, as well as other volatile compounds. Furthermore, the binding affinities and interactions of the n-hexane fraction's major metabolites were predicted against EGFR and BCL2 molecular targets using the molecular docking technique. These findings reveal the potential use of L. Sativum in the management of HCC.
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The chemical characterization of the extract of the aerial parts of Paronychia arabica afforded two oxetane containing lignans, paronychiarabicine A (1) and B (2), and one new megastigmane, paronychiarabicastigmane A (3), alongside a known lignan (4), eight known phenolic compounds (5-12), one known elemene sesquiterpene (13) and one steroid glycoside (14). The chemical structures of the isolated compounds were constructed based upon the HRMS, 1D, and 2D-NMR results. The absolute configurations were established via NOESY experiments as well as experimental and TDDFT-calculated electronic circular dichroism (ECD). Utilizing molecular docking, the binding scores and modes of compounds 1-3 towards the SARS-CoV-2 main protease (Mpro), papain-like protease (PLpro), and RNA-dependent RNA polymerase (RdRp) were revealed. Compound 3 exhibited a promising docking score (-9.8 kcal mol-1) against SARS-CoV-2 Mpro by forming seven hydrogen bonds inside the active site with the key amino acids. The reactome pathway enrichment analysis revealed a correlation between the inhibition of GSK3 and GSK3B genes (identified as the main targets of megastigmane treatment) and significant inhibition of SARS-CoV-1 viral replication in infected Vero E6 cells. Our results manifest a novel understanding of genes, proteins and corresponding pathways against SARS-CoV-2 infection and could facilitate the identification and characterization of novel therapeutic targets as treatments of SARS-CoV-2 infection.
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Breast cancer resistance protein (ABCG2) is a human ATP-binding cassette (ABC) that plays a paramount role in multidrug resistance (MDR) in cancer therapy. The discovery of ABCG2 inhibitors could assist in designing unprecedented therapeutic strategies for cancer treatment. There is as yet no approved drug targeting ABCG2, although a large number of drug candidates have been clinically investigated. In this work, binding affinities of 181 drug candidates in clinical-trial or investigational stages as ABCG2 inhibitors were inspected using in silico techniques. Based on available experimental data, the performance of AutoDock4.2.6 software was first validated to predict the inhibitor-ABCG2 binding mode and affinity. Combined molecular docking calculations and molecular dynamics (MD) simulations, followed by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations, were then performed to filter out the studied drug candidates. From the estimated docking scores and MM-GBSA binding energies, six auspicious drug candidates-namely, pibrentasvir, venetoclax, ledipasvir, avatrombopag, cobicistat, and revefenacin-exhibited auspicious binding energies with value < -70.0 kcal/mol. Interestingly, pibrentasvir, venetoclax, and ledipasvir were observed to show even higher binding affinities with the ABCG2 transporter with binding energies of < -80.0 kcal/mol over long MD simulations of 100 ns. The stabilities of these three promising candidates in complex with ABCG2 transporter were demonstrated by their energetics and structural analyses throughout the 100 ns MD simulations. The current study throws new light on pibrentasvir, venetoclax, and ledipasvir as curative options for multidrug resistant cancers by inhibiting ABCG2 transporter.
Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Benzimidazóis/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Fluorenos/química , Proteínas de Neoplasias/antagonistas & inibidores , Pirrolidinas/química , Sulfonamidas/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Benzimidazóis/metabolismo , Sítios de Ligação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Bases de Dados de Compostos Químicos , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos , Feminino , Fluorenos/metabolismo , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas de Neoplasias/metabolismo , Ligação Proteica , Pirrolidinas/metabolismo , Sulfonamidas/metabolismo , TermodinâmicaRESUMO
Wheat is a major nutritional cereal crop that has economic and strategic value worldwide. The sustainability of this extraordinary crop is facing critical challenges globally, particularly leaf rust disease, which causes endless problems for wheat farmers and countries and negatively affects humanity's food security. Developing effective marker-assisted selection programs for leaf rust resistance in wheat mainly depends on the availability of deep mining of resistance genes within the germplasm collections. This is the first study that evaluated the leaf rust resistance of 50 Egyptian wheat varieties at the adult plant stage for two successive seasons and identified the absence/presence of 28 leaf rust resistance (Lr) genes within the studied wheat collection. The field evaluation results indicated that most of these varieties demonstrated high to moderate leaf rust resistance levels except Gemmeiza 1, Gemmeiza 9, Giza162, Giza 163, Giza 164, Giza 165, Sids 1, Sids 2, Sids 3, Sakha 62, Sakha 69, Sohag 3 and Bany Swif 4, which showed fast rusting behavior. On the other hand, out of these 28 Lr genes tested against the wheat collection, 21 Lr genes were successfully identified. Out of 15 Lr genes reported conferring the adult plant resistant or slow rusting behavior in wheat, only five genes (Lr13, Lr22a, Lr34, Lr37, and Lr67) were detected within the Egyptian collection. Remarkedly, the genes Lr13, Lr19, Lr20, Lr22a, Lr28, Lr29, Lr32, Lr34, Lr36, Lr47, and Lr60, were found to be the most predominant Lr genes across the 50 Egyptian wheat varieties. The molecular phylogeny results also inferred the same classification of field evaluation, through grouping genotypes characterized by high to moderate leaf rust resistance in one cluster while being highly susceptible in a separate cluster, with few exceptions.
RESUMO
Coronavirus disease 2019 (COVID-19) is a new pandemic characterized by quick spreading and illness of the respiratory system. To date, there is no specific therapy for Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). Flavonoids, especially rutin, have attracted considerable interest as a prospective SARS-CoV-2 main protease (Mpro) inhibitor. In this study, a database containing 2017 flavone analogs was prepared and screened against SARS-CoV-2 Mpro using the molecular docking technique. According to the results, 371 flavone analogs exhibited good potency towards Mpro with docking scores less than -9.0 kcal/mol. Molecular dynamics (MD) simulations, followed by molecular mechanics-generalized Born surface area (MM/GBSA) binding energy calculations, were performed for the top potent analogs in complex with Mpro. Compared to rutin, PubChem-129-716-607 and PubChem-885-071-27 showed better binding affinities against SARS-CoV-2 Mpro over 150 ns MD course with ΔGbinding values of -69.0 and -68.1 kcal/mol, respectively. Structural and energetic analyses demonstrated high stability of the identified analogs inside the SARS-CoV-2 Mpro active site over 150 ns MD simulations. The oral bioavailabilities of probable SARS-CoV-2 Mpro inhibitors were underpinned using drug-likeness parameters. A comparison of the binding affinities demonstrated that the MM/GBSA binding energies of the identified flavone analogs were approximately three and two times less than those of lopinavir and baicalein, respectively. In conclusion, PubChem-129-716-607 and PubChem-885-071-27 are promising anti-COVID-19 drug candidates that warrant further clinical investigations.