scholarly journals In silico analysis to contemplate the chemistry behind gallic acid-mediated inhibition of Polyketide Synthase A from aflatoxin biosynthesis pathway of Aspergillus flavus

2021 ◽  
Author(s):  
Chhavi Thakur ◽  
Amanjot Singh Malhotra ◽  
Jata Shankar*
Keyword(s):  
Gallic Acid ◽  
Aspergillus Flavus ◽  
In Silico ◽  
Polyketide Synthase ◽  
Safety Concern ◽  
3D Structure ◽  
Hexanoic Acid ◽  
Binding Potential ◽  
Aflatoxin Biosynthesis ◽  
Carcinogenic Agent

Abstract Aspergillus flavus is known for producing the potent carcinogenic agent aflatoxin. Food contamination with aflatoxins is an important safety concern for agricultural yields. To identify and develop anti-aflatoxigenic agents, studies on phytochemicals as anti-aflatoxigenic agents have been documented including gallic acid. Thus, interaction studies using in-silico tools have been explored to understand the molecular mechanism behind inhibition of aflatoxin biosynthesis by studying the chemical interactions of gallic acid with polyketide synthase A (PksA) of A. flavus. The 3D structure of PksA consisting of seven domains was modeled using a Swiss-Model server followed by docking using Autodock tools-1.5.6 with substrate hexanoic acid and with that to gallic acid. The binding energy (electrostatic, inter-molecular or total internal energy) for gallic acid was lower (-6.09 to -4.79 kcal/mol) in comparison to hexanoic acid (-5.05 to -3.36 kcal/mol). During an interaction with the acyl transferase domain of PksA, both ligands showed H-bond formation at Glu36, Arg8, Thr11 positions. Ligplot analysis showed the formation of 7-H bonds in gallic acid and 3-H bonds in hexanoic acid. In addition, gallic acid showed stable binding with the active site of PksA indicated by steady root mean square deviation through molecular dynamic simulations. The chemistry between gallic acid and polyketide synthase A(PksA) exhibited that Gallic Acid possesses the highest level of binding potential (more number of hydrogen bonds) with PksA domain in comparison to hexanoic acid, a precursor for aflatoxin biosynthesis. Thus, we suggest enzymes from the aflatoxin biosynthetic pathway in aflatoxin-producing Aspergilli could be an important target for potential inhibitors.

scholarly journals In Silico Molecular Dynamics Docking of Drugs to the Inhibitory Active Site of SARS-CoV-2 Protease and Their Predicted Toxicology and ADME

2020 ◽  
Author(s):  
Leif Peterson
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bonds ◽  
Active Site ◽  
In Silico ◽  
Varicose Veins ◽  
3D Structure ◽  
Antiviral Drugs ◽  
Binding Potential ◽  
Strong Inhibitor ◽  
Experimental Drugs

<p></p><p>A in silico molecular dynamics (MD) docking investigation was conducted to identify drugs (ligands) which could potentially be of interest for repurposing. We sought ligands which formed the strongest binding potential energy with the x-ray crystallography-based active site of the SARS-CoV-2 protease C3Lpro. A total of 11,013 ligands were obtained from DrugBank. Because of the larger size of the active site of 3CLpro, we chose ligands whose molecular weight (MW) was greater than 400 (daltons) and less than 700, which resulted in 5,920 ligands. After correction of bonds and hydrogens, there were 4,634 ligands available for docking. Docking results indicate that the top 10 investigational and experimental drugs with binding energy (BE)≤-9 kcal/mol were Lorecivivint, Tivantinib, Omipalisib, DrugBank B08450, SRT-2104, R-428, DrugBank B01897, Bictegravir, Ridinilazole, and Itacitinib, while the top 10 approved drugs with BE≤-8.2 were Olaparib, Etoposide, Ouabain, Indinavir, Idelalisib, Trametinib, Lumacaftor, Ergotamine, Canagliflozin, and Edoxaban. There were two antiviral drugs among the top 30 hits, which were Bictegravir (investigational) and Indinavir (approved). The top 10 antivirals with BE≤-8.2 were Bictegravir, Tegobuvir, Filibuvir, Saquinavir, Fostemsavir, Indinavir, Temsavir, Pimodivir, Amenamevir, and Doravirine. Interestingly, the antiviral Remdesavir ranked low among the top 30 antivirals, since its BE was a low value of -7.5 kcal/mol. In silico toxicology and ADME (absorption, distribution, metabolism, excretion) prediction indicates that only 20% (6/30) of the top ligands were “drug-like,” and none were “lead-like,” since the lower bound of MW was 400. Another interesting finding was that the investigational natural supplement Diosmin (DrugBank ID B08995), used without prescription for varicose veins, ranked 22 overall (out of 3,896 with BE≤-6) with a strong BE=-8.8, and formed 8 hydrogen bonds with the active site for the putative best pose. Its energy-minimized 3D structure deeply penetrated and fully covered the width of the active site’s pocket. Diosmin had a lower BE than 97% of the top 30 antiviral drugs and formed more hydrogen bonds with the active site than 93% of the top 30 antivirals. Diosmin could therefore potentially serve as a strong inhibitor of the 3CLpro protease of SARS-CoV-2 and could be investigated in human clinical trials. Since a prescription is not required for its use, it could also be explored as a self-medicating natural alternative to prescribed synthetic drugs. Lastly, the green tea component epigallocatechin gallate (DrugBank ID B12116) also had a low BE=-8.3, and formed 2 hydrogen bonds with the active site, which was a BE that was better than 70% of the top 30 antivirals.</p><p></p>

scholarly journals In Silico Molecular Dynamics Docking of Drugs to the Inhibitory Active Site of SARS-CoV-2 Protease and Their Predicted Toxicology and ADME

2020 ◽  
Author(s):  
Leif Peterson
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bonds ◽  
Active Site ◽  
In Silico ◽  
Varicose Veins ◽  
3D Structure ◽  
Antiviral Drugs ◽  
Binding Potential ◽  
Strong Inhibitor ◽  
Experimental Drugs

<p></p><p>A in silico molecular dynamics (MD) docking investigation was conducted to identify drugs (ligands) which could potentially be of interest for repurposing. We sought ligands which formed the strongest binding potential energy with the x-ray crystallography-based active site of the SARS-CoV-2 protease C3Lpro. A total of 11,013 ligands were obtained from DrugBank. Because of the larger size of the active site of 3CLpro, we chose ligands whose molecular weight (MW) was greater than 400 (daltons) and less than 700, which resulted in 5,920 ligands. After correction of bonds and hydrogens, there were 4,634 ligands available for docking. Docking results indicate that the top 10 investigational and experimental drugs with binding energy (BE)≤-9 kcal/mol were Lorecivivint, Tivantinib, Omipalisib, DrugBank B08450, SRT-2104, R-428, DrugBank B01897, Bictegravir, Ridinilazole, and Itacitinib, while the top 10 approved drugs with BE≤-8.2 were Olaparib, Etoposide, Ouabain, Indinavir, Idelalisib, Trametinib, Lumacaftor, Ergotamine, Canagliflozin, and Edoxaban. There were two antiviral drugs among the top 30 hits, which were Bictegravir (investigational) and Indinavir (approved). The top 10 antivirals with BE≤-8.2 were Bictegravir, Tegobuvir, Filibuvir, Saquinavir, Fostemsavir, Indinavir, Temsavir, Pimodivir, Amenamevir, and Doravirine. Interestingly, the antiviral Remdesavir ranked low among the top 30 antivirals, since its BE was a low value of -7.5 kcal/mol. In silico toxicology and ADME (absorption, distribution, metabolism, excretion) prediction indicates that only 20% (6/30) of the top ligands were “drug-like,” and none were “lead-like,” since the lower bound of MW was 400. Another interesting finding was that the investigational natural supplement Diosmin (DrugBank ID B08995), used without prescription for varicose veins, ranked 22 overall (out of 3,896 with BE≤-6) with a strong BE=-8.8, and formed 8 hydrogen bonds with the active site for the putative best pose. Its energy-minimized 3D structure deeply penetrated and fully covered the width of the active site’s pocket. Diosmin had a lower BE than 97% of the top 30 antiviral drugs and formed more hydrogen bonds with the active site than 93% of the top 30 antivirals. Diosmin could therefore potentially serve as a strong inhibitor of the 3CLpro protease of SARS-CoV-2 and could be investigated in human clinical trials. Since a prescription is not required for its use, it could also be explored as a self-medicating natural alternative to prescribed synthetic drugs. Lastly, the green tea component epigallocatechin gallate (DrugBank ID B12116) also had a low BE=-8.3, and formed 2 hydrogen bonds with the active site, which was a BE that was better than 70% of the top 30 antivirals.</p><p></p>

scholarly journals DESIGN AND SCREENING OF GALLIC ACID DERIVATIVES AS INHIBITORS OF MALARIAL DIHYDROFOLATE REDUCTASE (DHFR) BY IN SILICO DOCKING

2017 ◽  
Vol 10 (2) ◽  
pp. 330 ◽  
Author(s):  
Ade Arsianti Arsianti ◽  
Hendri Astuty ◽  
Fadilah Fadilah ◽  
Anton Bahtiar ◽  
Hiroki Tanimoto ◽  
...  
Keyword(s):  
Gallic Acid ◽  
Dihydrofolate Reductase ◽  
In Silico ◽  
3D Structure ◽  
Geometry Optimization ◽  
Docking Study ◽  
Open Chain ◽  
In Silico Docking ◽  
High Prevalence ◽  
Infection Disease

Objective: Malaria is an infection disease caused by plasmodium parasite with high prevalence in tropic and subtropic countries. The aim of this work was to design and screening of  gallic acid derivatives as inhibitors of malarial dihydrofolate reductase (DHFR) by in silico docking.Methods: The derivatives were designed by expanding the carboxyl group of gallic acid with open-chain moiety of L-threonine-allyl esters, as well as to modify the hydroxy groups on the aromatic ring of gallic acid with methoxyl group in the derivatives.  In silico approach has been utilized in finding the potential antimalaria of gallic acid derivatives. Fourteen Gallic acid derivatives (compound 2-15) were modeled into 3D structures by  ACD Labs software. Geometry optimization and minimization of energy 3D structure of gallic acid derivatives as ligands using the MOE software.  Docking process and amino acid analysis were executed by using MOE software. Results: In silico docking study resulted in the three top-ranked compounds, namely compound 5, 8 and 12. Among those three top-ranked compounds, compound 12 (octyl gallate), exhibited the strongest interaction and greatest inhibitory activity against the receptor of malarial DHFR.Conclusion Our results clearly demonstrated that compound 12 (octyl gallate) could be developed as a promising candidate for  the new anti-malarial agent.   

Aspergillus flavus aflatoxin occurrence and expression of aflatoxin biosynthesis genes in soil

2008 ◽  
Vol 54 (5) ◽  
pp. 371-379 ◽  
Author(s):  
Cesare Accinelli ◽  
H.K. Abbas ◽  
R.M. Zablotowicz ◽  
J.R. Wilkinson
Keyword(s):  
Aspergillus Flavus ◽  
Crop Residue ◽  
Safety Concern ◽  
Polymerase Chain Reaction Analysis ◽  
Aflatoxin Biosynthesis ◽  
Cultural Methods ◽  
Loam Soil ◽  
Series Of Experiments ◽  
Polymerase Chain ◽  
Corn Residues

The carcinogen aflatoxin B1 (AFB1) produced by Aspergillus flavus is a major food safety concern in crops. However, information on AFB1 occurrence in soil and crop residue is scarce. A series of experiments investigated the occurrence of AFB1 in soil and corn residues and ascertained the ecology of A. flavus in a Dundee silt loam soil. Samples of untilled soil (0–2 cm) and residues were collected in March 2007 from plots previously planted with a corn isoline containing the Bacillus thuringiensis (Bt) endotoxin gene or the parental non-Bt isoline. AFB1 levels were significantly different in various corn residues. The highest AFB1 levels were observed in cobs containing grain, with 145 and 275 ng·g–1in Bt and non-Bt, respectively (P ≥ F = 0.001). Aflatoxin levels averaged 3.3 and 9.6 ng·g–1in leaves and (or) stalks and cobs without grain, respectively. All soils had AFB1 ranging from 0.6 to 5.5 ng·g–1with similar levels in plots from Bt and non-Bt corn. Based on cultural methods, soil contained from log103.1 to 4.5 A. flavus cfu·g–1with about 60% of isolates producing aflatoxin. Laboratory experiments demonstrated that AFB1 is rapidly degraded in soil at 28 °C (half-life ≤ 5 days). The potential of the soil A. flavus to produce aflatoxins was confirmed by molecular methods. Transcription of 5 aflatoxin biosynthesis genes, including aflD, aflG, aflP, aflR, and aflS, were detected by reverse transcription – polymerase chain reaction analysis in soil. Although AFB1 appears to be transient in soils, it is clear that AFB1 is produced in surface soil in the presence of corn residues, as indicated by A. flavus cfu levels, AFB1 detection, and expression of aflatoxin biosynthetic genes.

Increased sensitivity of Aspergillus flavus and Aspergillus parasiticus aflatoxin biosynthesis polyketide synthase mutants to UVB light

2010 ◽  
Vol 3 (3) ◽  
pp. 263-270 ◽  
Author(s):  
K. Ehrlich ◽  
Q. Wei ◽  
D. Bhatnagar
Keyword(s):  
Aspergillus Flavus ◽  
Polyketide Synthase ◽  
Aspergillus Parasiticus ◽  
Aflatoxin Contamination ◽  
Aflatoxin Biosynthesis ◽  
Increased Sensitivity ◽  
Isogenic Mutants

One strategy to reduce aflatoxin contamination of maize and cottonseed is to introduce spores of non-aflatoxigenic strains as competitors. Using isogenic mutants we show that, upon 5 or 20 min exposure to 302 nm (UVB) light, the viability of conidia of Aspergillus flavus and Aspergillus parasiticus mutants lacking the ability to accumulate any aflatoxin precursor metabolite is reduced five-fold compared to that of aflatoxin-producing strains or pigmented mutants that accumulate aflatoxin precursors. This result suggests that the long-term viability of introduced non-aflatoxigenic competitor strains may be lower than that of natural aflatoxin-producing isolates when exposed to sunlight.

Chemical Composition and Active Properties Evaluation of Wild Oregano (Origanum Vulgare) and Ginger (Zingiber Officinale-Roscoe) Essential Oils

2018 ◽  
Vol 69 (8) ◽  
pp. 1927-1933 ◽  
Author(s):  
Mariana Deleanu ◽  
Elisabeta E. Popa ◽  
Mona E. Popa
Keyword(s):  
Essential Oil ◽  
Growth Inhibition ◽  
Gallic Acid ◽  
Aspergillus Flavus ◽  
Zingiber Officinale ◽  
Penicillium Expansum ◽  
Origanum Vulgare ◽  
Zingiber Officinale Roscoe ◽  
Oregano Oil ◽  
Gallic Acid Equivalent

The compounds in Ginger (Zingiber officinale-Roscoe) essential oil provenience China and wild oregano (Origanum vulgare) essential oil of Romanian origin were identified by GC/MS and their antioxidant and antifungal properties were evaluated. Wild oregano oil was characterized by high content of oxygenated monoterpenes hydrocarbons (84.05%) of which carvacrol was the most abundant (73.85%) followed by b-linalool (3.46%) and thymol (2.29%). Ginger oil had a higher content of sesquiterpene hydrocarbons including zingiberene (31.47%), b-sesquiphellandrene (13.76%), a-curcumene (10.41%), a-farnesene (8.31%) and b-bisabolene (7.55%) but a lower content of oxygenated monoterpenes (7.97%). The high content of oxygenated monoterpens of wild oregano oil is in accordance with total content of polyphenols determined by the Folin�Ciocalteu method (6.71�0.73 mg of gallic acid equivalent per g oil). Ginger oil had only 1.34�0.22 mg gallic acid equivalent per g oil. Wild oregano oils exhibited appreciable in vitro antioxidant activity as assessed by 2, 2`-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and 2,2�-azino-bis (3 ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS). The sample concentration required to scavenge 50% of the DPPH free radicals was 0.76�0.13 mg/mL for wild oregano oil compared to 20.22�2.12 mg/mL for ginger oil. Also, wild oregano oils showed significant inhibitory activity against selected pathogenic fungi (Fusarium oxysporum, Aspergillus flavus and Penicillium expansum). 1�L of oregano oil is sufficient for almost 75% growth inhibition of Aspergillus flavus compared to ginger oil which shows antifungal activity at 240�L for 78% growth inhibition. It can be concluded that wild oregano oil could be used as food preservative in some food products in which Fusarium oxysporum, Aspergillus flavus and Penicillium expansum could grow and have potential to produce health hazards mycotoxines.

Carbon catabolite repression gene creA regulates morphology, aflatoxin biosynthesis and virulence in Aspergillus flavus

2018 ◽  
Vol 115 ◽  
pp. 41-51 ◽  
Author(s):  
Opemipo Esther Fasoyin ◽  
Bin Wang ◽  
Mengguang Qiu ◽  
Xiaoyun Han ◽  
Kuang-Ren Chung ◽  
...  
Keyword(s):  
Aspergillus Flavus ◽  
Catabolite Repression ◽  
Carbon Catabolite Repression ◽  
Aflatoxin Biosynthesis

scholarly journals Elucidating Binding Sites and Affinities of ERα Agonist and Antagonist to Human Alpha-Fetoprotein by in silico Modeling and Point Mutagenesis

2019 ◽  
Author(s):  
Nurbubu T. Moldogazieva ◽  
Daria S. Ostroverkhova ◽  
Nikolai N. Kuzmich ◽  
Vladimir V. Kadochnikov ◽  
Alexander A. Terentiev ◽  
...  
Keyword(s):  
Binding Sites ◽  
In Silico ◽  
Disulfide Bonds ◽  
Electrostatic Interactions ◽  
Molecular Mechanisms ◽  
3D Structure ◽  
Scoring Function ◽  
Alpha Fetoprotein ◽  
Ligand Interaction ◽  
Ligand Interactions

Alpha-fetoprotein (AFP) is a major embryo- and tumor-associated protein capable of binding and transporting variety of hydrophobic ligands including estrogens. AFP has been shown to inhibit estrogen receptor (ER)-positive tumor growth and this can be attributed to its estrogen-binding ability. Despite AFP has long been investigated, its three-dimensional (3D) structure has not been experimentally resolved and molecular mechanisms underlying AFP-ligand interaction remain obscure. In our study we constructed homology-based 3D model of human AFP (HAFP) with the purpose to perform docking of ER&alpha; ligands, three agonists (17&beta;-estradiol, estrone and diethylstilbestrol) and three antagonists (tamoxifen, afimoxifene and endoxifen) into the obtained structure. Based on ligand docked scoring function, we identified three putative estrogen- and antiestrogen-binding sites with different ligand binding affinities. Two high-affinity sites were located in (i) a tunnel formed within HAFP subdomains IB and IIA and (ii) opposite side of the molecule in a groove originating from cavity formed between domains I and III, while (iii) the third low-affinity site was found at the bottom of the cavity. 100 ns MD simulation allowed studying their geometries and showed that HAFP-estrogen interactions occur due to van der Waals forces, while both hydrophobic and electrostatic interactions were almost equally involved in HAFP-antiestrogen binding. MM/GBSA rescoring method estimated binding free energies (&Delta;Gbind) and showed that antiestrogens have higher affinities to HAFP as compared to estrogens. We performed in silico point substitutions of amino acid residues to confirm their roles in HAFP-ligand interactions and showed that Thr132, Leu138, His170, Phe172, Ser217, Gln221, His266, His316, Lys453, and Asp478 residues along two disulfide bonds, Cys224-Cys270 and Cys269-Cys277 have key roles in both HAFP-estrogen and HAFP-antiestrogen binding. Data obtained in our study contribute to understanding mechanisms underlying protein-ligand interactions and anti-cancer therapy strategies based on ER-binding ligands.

scholarly journals Vibrio gazogenes inhibits aflatoxin production through downregulation of aflatoxin biosynthetic genes in Aspergillus flavus

2022 ◽  
Author(s):  
Shyam L. Kandel ◽  
Rubaiya Jesmin ◽  
Brian M. Mack ◽  
Rajtilak Majumdar ◽  
Matthew K. Gilbert ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Secondary Metabolite ◽  
Aspergillus Flavus ◽  
Fungal Biomass ◽  
Expression Profiles ◽  
Health Hazard ◽  
Gene Clusters ◽  
Aflatoxin Contamination ◽  
Aflatoxin Biosynthesis ◽  
Control Samples

Aspergillus flavus is an opportunistic pathogen of oilseed crops such as maize, peanut, cottonseed, and tree nuts and produces carcinogenic secondary metabolites known as aflatoxins during seed colonization. Aflatoxin contamination not only reduces the value of the produce but also is a health hazard to humans and animals. Previously, we observed inhibition of A. flavus aflatoxin biosynthesis upon exposure to the marine bacterium, Vibrio gazogenes (Vg). In this study, we used RNA sequencing to examine the transcriptional profiles of A. flavus treated with both live and heat-inactivated dead Vg and control samples. Fungal biomass, total accumulated aflatoxins, and expression profiles of genes constituting secondary metabolite biosynthetic gene clusters were determined at 24, 30, and 40 h after treatment. Statistically significant reductions in total aflatoxins were detected in Vg-treated samples as compared to control samples at 40 h. But no statistical difference in fungal biomass was observed upon these treatments. The Vg treatments were most effective on aflatoxin biosynthesis as was reflected in significant downregulation of majority of the genes in the aflatoxin gene cluster including the aflatoxin pathway regulator gene, aflR. Along with aflatoxin genes, we also observed significant downregulation in some other secondary metabolite gene clusters including cyclopiazonic acid and aflavarin, suggesting that the treatment may inhibit other secondary metabolites as well. Finally, a weighted gene correlation network analysis identified an upregulation of ten genes that were most strongly associated with Vg-dependent aflatoxin inhibition and provide a novel start-point in understanding the mechanisms that result in this phenomenon.

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