Antimyotoxic Activity of Synthetic Peptides Derived from Bothrops atrox Snake Gamma Phospholipase A2 Inhibitor Selected by Virtual Screening

2019 ◽  
Vol 19 (22) ◽  
pp. 1952-1961 ◽  
Author(s):  
J.C. Sobrinho ◽  
A.F. Francisco ◽  
R. Simões-Silva ◽  
A.M. Kayano ◽  
J.J. Alfonso Ruiz Diaz ◽  
...  
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
Synthetic Peptides ◽  
Cell Damage ◽  
Neutralization Assay ◽  
Phospholipase Activity ◽  
Phospholipases A2 ◽  
Catalytically Active ◽  
Bothrops Atrox

Background: Several studies have aimed to identify molecules that inhibit the toxic actions of snake venom phospholipases A2 (PLA2s). Studies carried out with PLA2 inhibitors (PLIs) have been shown to be efficient in this assignment. Objective: This work aimed to analyze the interaction of peptides derived from Bothrops atrox PLIγ (atPLIγ) with a PLA2 and to evaluate the ability of these peptides to reduce phospholipase and myotoxic activities. Methods: Peptides were subjected to molecular docking with a homologous Lys49 PLA2 from B. atrox venom modeled by homology. Phospholipase activity neutralization assay was performed with BthTX-II and different ratios of the peptides. A catalytically active and an inactive PLA2 were purified from the B. atrox venom and used together in the in vitro myotoxic activity neutralization experiments with the peptides. Results: The peptides interacted with amino acids near the PLA2 hydrophobic channel and the loop that would be bound to calcium in Asp49 PLA2. They were able to reduce phospholipase activity and peptides DFCHNV and ATHEE reached the highest reduction levels, being these two peptides the best that also interacted in the in silico experiments. The peptides reduced the myotubes cell damage with a highlight for the DFCHNV peptide, which reduced by about 65%. It has been suggested that myotoxic activity reduction is related to the sites occupied in the PLA2 structure, which could corroborate the results observed in molecular docking. Conclusion: This study should contribute to the investigation of the potential of PLIs to inhibit the toxic effects of PLA2s.

scholarly journals Inhibition of secreted phospholipases A2 by 2-oxoamides based on α-amino acids: Synthesis, in vitro evaluation and molecular docking calculations

2011 ◽  
Vol 19 (2) ◽  
pp. 735-743 ◽  
Author(s):  
Varnavas D. Mouchlis ◽  
Victoria Magrioti ◽  
Efrosini Barbayianni ◽  
Nathan Cermak ◽  
Rob C. Oslund ◽  
...  
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
In Vitro Evaluation ◽  
Phospholipases A2 ◽  
Docking Calculations

scholarly journals Interaction of wild-type signal sequences and their charged variants with model and natural membranes

1993 ◽  
Vol 293 (1) ◽  
pp. 43-49 ◽  
Author(s):  
N M Rao ◽  
R Nagaraj
Keyword(s):  
Amino Acids ◽  
Synthetic Peptides ◽  
Model Membranes ◽  
Signal Peptides ◽  
Wild Type ◽  
Signal Sequences ◽  
Hydrophobic Region ◽  
Phospholipases A2 ◽  
Charged Amino Acids

The interaction of synthetic peptides corresponding to wild-type signal sequences, and their mutants having charged amino acids in the hydrophobic region, with model and natural membranes has been studied. At high peptide concentrations, i.e. low lipid/peptide ratios, the signal peptides cause release of carboxyfluorescein (CF) from model membranes with lipid compositions corresponding to those of translocation-competent as well as translocation-incompetent membranes. Interestingly, mutant sequences, which were non-functional in vivo, caused considerable release of CF compared with the wild-type sequences. Both wild-type and mutant signal sequences perturb model membranes even at lipid/peptide ratios of 1000:1, as indicated by the activities of phospholipases A2, C and D. These studies indicate that such mutant signals are non-functional not because of their inability to interact with membranes, but due to defective targeting to the membrane. The signal peptides inhibit phospholipase C activity in microsomes, uncouple oxidative phosphorylation in mitochondria and increase K+ efflux from erythrocytes, and one of the mutant sequences is a potent degranulator of the mast cells. Both wild-type and mutant signal sequences have the ability to perturb vesicles of various lipid compositions. With respect to natural membranes, the peptides do not show any bias towards translocation-competent membranes.

scholarly journals The interaction of small domains between the subunits of phosphatidylinositol 3-kinase determines enzyme activity.

1994 ◽  
Vol 14 (4) ◽  
pp. 2675-2685 ◽  
Author(s):  
A Klippel ◽  
J A Escobedo ◽  
M Hirano ◽  
L T Williams
Keyword(s):  
Amino Acids ◽  
Catalytic Domain ◽  
Specific Interaction ◽  
Sh2 Domains ◽  
Catalytically Active ◽  
Functional Complex ◽  
Src Homology ◽  
Carboxy Terminal

Previous studies have suggested that the two subunits of phosphatidylinositol (PI) 3-kinase, p85 and p110, function as localizing and catalytic subunits, respectively. Using recombinant p85 and p110 molecules, we have reconstituted the specific interaction between the two subunits of mouse PI 3-kinase in cells and in vitro. We have previously shown that the region between the two Src homology 2 (SH2) domains of p85 is able to form a functional complex with the 110-kDa subunit in vivo. In this report, we identify the corresponding domain in p110 which directs the binding to p85. We demonstrate that the interactive domains in p85 and p110 are less than 103 and 124 amino acids, respectively, in size. We also show that the association of p85 and p110 mediated by these domains is critical for PI 3-kinase activity. Surprisingly, a complex between a 102-amino-acid segment of p85 and the full-length p110 molecule is catalytically active, whereas p110 alone has no activity. In addition to the catalytic domain in the carboxy-terminal region, 123 amino acids at the amino terminus of p110 were required for catalytic activity and were sufficient for the interaction with p85. These results indicate that the 85-kDa subunit, previously thought to have only a linking role in localizing the p110 catalytic subunit, is an important component of the catalytic complex.

scholarly journals Inhibition of proteases and phospholipases A2 from Bothrops atrox and Crotalus durissus terrificus snake venoms by ascorbic acid, vitamin E, and B-complex vitamins

2016 ◽  
Vol 88 (3 suppl) ◽  
pp. 2005-2016 ◽  
Author(s):  
CARLOS H.M. OLIVEIRA ◽  
ANDERSON A. SIMÃO ◽  
MARCUS V.C. TRENTO ◽  
PEDRO H.S. CÉSAR ◽  
SILVANA MARCUSSI
Keyword(s):  
Vitamin E ◽  
Low Cost ◽  
Crotalus Durissus Terrificus ◽  
Phospholipases A2 ◽  
Antioxidant Mechanism ◽  
Valuable Adjunct ◽  
B Complex Vitamins ◽  
Crotalus Durissus ◽  
Bothrops Atrox

ABSTRACT The enzyme inhibition by natural and/ or low-cost compounds may represent a valuable adjunct to traditional serotherapy performed in cases of snakebite, mainly with a view to mitigate the local effects of envenoming. The objective of this study was to evaluate possible interactions between vitamins and enzymes that comprise Bothrops atrox and Crotalus durissus terrificus venoms, in vitro. Proteolysis inhibition assays (substrates: azocasein, collagen, gelatin and fibrinogen), hemolysis, coagulation, hemagglutination were carried out using different proportions of vitamins in face of to inhibit minimum effective dose of each venom. The vitamins were responsible for reducing 100% of breaking azocasein by C.d.t. venom, thrombolysis induced by B. atrox and fibrinogenolysis induced by both venoms. It is suggested the presence of interactions between vitamin and the active site of enzymes, for example the interactions between hydrophobic regions present in the enzymes and vitamin E, as well as the inhibitions exercised by antioxidant mechanism.

scholarly journals In Vitro and In Silico Evaluation of Biological Properties of Some 1, 3, 4-Oxadiazole Derivatives Against Streptococcus mutans and Their Interaction With Gbp-C by Molecular Docking

2021 ◽  
Vol 13 (4) ◽  
pp. 142-147
Author(s):  
Behin Omidi ◽  
Yasin SarveAhrabi
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
Hydrogen Bonds ◽  
Streptococcus Mutans ◽  
In Silico ◽  
Antibacterial Properties ◽  
Inhibition Zone ◽  
Biological Properties ◽  
High Concentrations

Background: The need to replace new drug structures for the treatment of resistant strains has become essential. Streptococcus mutans is one of the most important factors in causing tooth decay. Glucan binding protein-C (Gbp-C) is a crucial mobileular floor protein that is worried in biofilm formation, and 1, 3, 4-oxadiazoles are new antibacterial structures. Accordingly, this study focused on assessing in vitro and in silico activity of our previously synthesized compounds of 1, 3, 4-oxadiazole against S. mutans. Methods: To this end, our previously synthesized derivatives were re-synthesized and prepared, and then antibacterial susceptibility tests were used for inhibition zone, minimum inhibitory concentration (MIC), and minimum bactericidal concentration (MBC) test values. The molecular docking method was also applied to confirm the effect of compounds in interaction with the Gbp-C of S. mutans. Results: All compounds showed different effects against the bacterial sample. Among these, the most effective ones were related to naphthalene (4d), fluorophenyl (4e), and dimethoxyphenyl (4h) derivatives against S. mutans, respectively. Other compounds also had antibacterial properties but to a lesser extent. In the molecular part, compounds 4d and 4h had the highest affinity to inhibit the GbpC-protein. compound 4d with amino acids ASP and GLN established 402 and 391 hydrogen bonds, respectively, and compound 4h with amino acids SER, GLU, THR, and TRP established 347, 360, 449, and 451 hydrogen bonds, respectively. Conclusions: In general, 1, 3, 4-oxadiazoles containing naphthalene and dimethoxy phenyl functional groups in high concentrations can be good alternatives to the existing drugs for eliminating caries-causing tooth mutants that have drug resistance. It seems that more inhibitory effects can be observed on clinical specimens by adding different purposeful groups and increasing the destructive power of oxadiazole-based compounds.

scholarly journals An immunoinformatics study: designing multivalent T-cell epitope vaccine against canine circovirus

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Pankaj Jain ◽  
Amit Joshi ◽  
Nahid Akhtar ◽  
Sunil Krishnan ◽  
Vikas Kaushik
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Molecular Docking ◽  
In Silico ◽  
Cell Epitope ◽  
Cost Effective ◽  
Dynamics Simulation ◽  
Cloning And Expression

Abstract Background Canine circovirus is a deadly pathogen of dogs and causes vasculitis and hemorrhagic enteritis. It causes lethal gastroenteritis in pigs, fox, and dogs. Canine circovirus genome contains two main (and opposite) transcription units which encode two open reading frames (ORFs), a replicase-associated protein (Rep) and the capsid (Cap) protein. The replicase protein and capsid protein consist of 303 amino acids and 270 amino acids respectively. Several immuno-informatics methods such as epitope screening, molecular docking, and molecular-dynamics simulations were used to craft peptide-based vaccine construct against canine circovirus. Results The vaccine construct was designed by joining the selected epitopes with adjuvants by suitable linker. The cloning and expression of the vaccine construct was also performed using in silico methods. Screening of epitopes was conducted by NetMHC server that uses ANN (Artificial neural networking) algorithm. These methods are fast and cost-effective for screening epitopes that can interact with dog leukocyte antigens (DLA) and initiate an immune response. Overall, 5 epitopes, YQHLPPFRF, YIRAKWINW, ALYRRLTLI, HLQGFVNLK, and GTMNFVARR, were selected and used to design a vaccine construct. The molecular docking and molecular dynamics simulation studies show that these epitopes can bind with DLA molecules with stability. The codon adaptation and in silico cloning studies show that the vaccine can be expressed by Escherichia coli K12 strain. Conclusion The results suggest that the vaccine construct can be useful in preventing the dogs from canine circovirus infections. However, the results need further validation by performing other in vitro and in vivo experiments.

Xanthone Conjugated Amino Acids as Potential Anticancer and DNA Binding Agents: Molecular Docking, Cytotoxicity and SAR Studies

2019 ◽  
Vol 18 (15) ◽  
pp. 2169-2177 ◽  
Author(s):  
Kadallipura P. Rakesh ◽  
Nanjudappa Darshini ◽  
Honnayakanakalli M. Manukumar ◽  
Hamse K. Vivek ◽  
Mohammed Y.H. Eissa ◽  
...  
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
Dna Binding ◽  
Anticancer Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Molecular Surface ◽  
Heterocyclic Molecules

Background: Amino acids conjugated with heterocyclic molecules are well known for their effective bioactive properties. In search of effective anticancer agents, a series of xanthone linked amino acids 2-23 were synthesized and tested for in vitro anticancer activity. Methods: In vitro anticancer activity of the synthesized xanthone linked amino acids 2-23 are tested against three different cancer cell lines MCF-7, MDA-MB-435 and A549 by MTT assay and validated by DNA binding and molecular docking approaches. Doxorubicin and ethidium bromide used as standard and positive control respectively. Results: Compounds 7, 8 and 9 exhibited potent anticancer activity against tested cancer cell lines and DNA binding study using methyl green. In the molecular docking study, binding interactions of the most active compounds 7, 8 and 9 were confirmed to molecular surface of DNA. Conclusion: Structure-Activity Relationship (SAR) showed that the aromatic and hydrophobic amino acids (phenylalanine, tyrosine, and tryptophan) favoured the DNA binding studies and anticancer activity whereas, aliphatic amino acids showed least anticancer activity.

scholarly journals Design and Identification of Lead Compounds Targeting Nipah G Attachment Glycoprotein by In Silico Approaches

2021 ◽  
pp. 156-169
Author(s):  
Jainey P. James ◽  
. Apoorva ◽  
Shreya Renita Monteiro ◽  
K. B. Sukesh ◽  
A. Varun
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
Nipah Virus ◽  
In Vitro Models ◽  
Asian Countries ◽  
Docking Score ◽  
Lead Compounds ◽  
Computational Screening ◽  
Kerala State

Nipah virus (NiV) caused several outbreaks in Asian countries, including the latest one from the Kerala state of India. There is no drug available against NiV till now, despite its urgent requirement. There are reports about the anti-influenza viral drug Favipiravir, which has positively affected the Nipah virus in vitro models. In the current work, we have provided a computational screening for NiV inhibitors. Twenty-two designed compounds from favipiravir and Nipah glycoprotein, 3D11, were chosen and performed molecular docking to analyse the various conformations and interactions with the amino acids; further, their physicochemical and ADMET properties were also computed. The compound 5_Favipiravir have an excellent docking score (-6.16 kcal/mol), followed by compound 4_Favipiravir and 19_Favipiravir with docking score of -5.50 and -5.38 kcal/mol respectively. The three compounds had the respective heterocyclic moieties such as pyrazole, imidazole and pyrazinone. All the twenty-two designed compounds obey the Lipinski rule of five, which infer that they will not have problems with oral bioavailability.  Thus, it is concluded that the incorporated heterocyclic groups in favipiravir can add to the anti-Nipah activity; hence it can act as future leads for the treatment for the disease caused by Nipah virus.

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