Insight into molecular interactions of Aβ peptide and gelatinase from Enterococcus faecalis: a molecular modeling approach

Jalkute, Chidambar B.; Barage, Sagar H.; Sonawane, Kailas D.

doi:10.1039/c4ra09354b

Cited by 22 publications

(18 citation statements)

References 87 publications

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“…The various anti‐aggregation agents that include small molecules, nanoparticles, peptides, and degrading enzymes have been recently reported. In search of Aβ 42 aggregation inhibitors, the role of small organic molecules against Aβ 42 fibrillation is considered crucial .…”

Section: Introductionmentioning

confidence: 99%

Molecular insights into Aβ₄₂ protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study

Saini

Shuaib

Goyal

2017

J of Molecular Recognition

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The aggregation of amyloid β-peptide (Aβ ) into toxic oligomers, fibrils, has been identified as a key process in Alzheimer's disease (AD) progression. The role of halogen-substituted compounds have been highlighted in the disassembly of Aβ protofibril. However, the underlying inhibitory mechanism of Aβ protofibril destabilization remains elusive. In this regard, a combined molecular docking and molecular dynamics (MD) simulations were performed to elucidate the inhibitory mechanism of a fluorinated compound, D744, which has been reported previously for potential in vitro and in vivo inhibitory activity against Aβ aggregation and reduction in the Aβ-induced cytotoxicity. The molecular docking analysis highlights that D744 binds and interacts with chain A of the protofibril structure with hydrophobic contacts and orthogonal multipolar interaction. MD simulations reveal destabilization of the protofibril structure in the presence of D744 due to the decrease in β-sheet content and a concomitant increase of coil and bend structures, increase in the interchain D23-K28 salt bridge distance, decrease in the number of backbone hydrogen bonds, increase in the average distance between Cα atoms, and decrease in the binding affinity between chains A and B of the protofibril structure. The binding free-energy analysis between D744 and the protofibril structure with Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) reveal that residues Leu17, Val18, Phe19, Phe20, Ala21, Glu22, Asp23, Leu34, Val36, Gly37, and Gly38 of chain A of the protofibril structure contribute maximum towards binding free energy (ΔG = -44.87 kcal/mol). The insights into the underlying inhibitory mechanism of small molecules that show potential in vitro anti-aggregation activity against Aβ will be beneficial for the current and future AD therapeutic studies.

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Section: Introductionmentioning

confidence: 99%

Molecular insights into Aβ₄₂ protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study

Saini

Shuaib

Goyal

2017

J of Molecular Recognition

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“…All docked complexes are subjected to 30 ns MD simulations in order to find out the stability of different AKs in presence of ZINC71575479. GROMACS utilities RMSD, RMSF, and R g are used to check the stability of all four complex and control as like earlier studies . The RMSD is an important parameter used to analyze the output obtained from MD trajectories.…”

Section: Resultsmentioning

confidence: 99%

“…GROMACS utilities RMSD, RMSF, and R g are used to check the stability of all four complex and control as like earlier studies. [59][60][61][62] The RMSD is an important parameter used to analyze the output obtained from MD trajectories. RMSD of the protein backbone atoms are plotted as a function of time to check the stability of each complex throughout the simulation.…”

Section: Molecular Dynamics Simulationmentioning

confidence: 99%

Molecular modeling studies to explore the binding affinity of virtually screened inhibitor toward different aminoglycoside kinases from diverse MDR strains

Parulekar

Sonawane

2017

J of Cellular Biochemistry

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Antibiotic resistance to aminoglycoside group of antibiotics mainly occurs by aminoglycoside kinases (AKs). Thus, targeting AKs from different multidrug resistant (MDR) strains could result into inhibition of AK enzymes and ultimately the resistance. Therefore, the present study aims to target one of these AKs that is APH(3')-Ia from Acinetobacter baumannii through structure based virtual screening (SBVS) and test the binding affinity of the most stable virtually screened inhibitor with AKs from Mycobacterium tuberculosis, Acinetobacter baumannii, Enterococcus gallinarum, and Escherichia coli. SBVS investigated ZINC71575479 as a most stable inhibitor with -8.92 kcal/mol of binding energy and 0.66 µM of inhibition constant. Molecular docking results revealed that the ZINC71575479 can efficiently bind to nucleotide triphosphate (NTP) binding site of different AKs which is a known drug target site. Sequence analysis study of different AKs showed no significant similarity for active site residues; however structure superimposition study showed conserved NTP-binding domain. Molecular dynamics (MD) simulations showed stable behavior of all docked complexes with notable conformational stability of salt bridges at NTP-binding site of different AKs. Binding energy calculations revealed the interactions between key residues from NTP- binding domain of different AKs with ZINC71575479. In order to validate the MD simulations and binding energy results, crystal structure complexed with tyrphostin AG1478 a known inhibitor of AKs was kept as control. Thus, this work demonstrates the binding efficiency of ZINC71575479 toward different AKs for circumventing aminoglycoside resistance and opens avenues for the development of new antibiotics that can target diverse MDR strains with aminoglycoside resistance.

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“…Molecular docking is a worthwhile method to explore protein and ligand interactions at the molecular level [15]. The method was used to study the binding of ligands to heme and plasmodium falciparum L-lactate dehydrogenase (pLDH).…”

Section: Receptor Structure Preparation and Generation Of Grid Box Fomentioning

confidence: 99%

In silico and in vivo anti-malarial investigation on [(5-nitroheteroaryl-2-yl) methylidene] hydrazinyl hetroaryl derivatives

Tahghighi

Mohamadi-Zarch

Rahimi

et al. 2020

Preprint

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Abstract Background Today, the resistance to Plasmodium falciparum against common anti-malarial drugs has attracted the attention towards the alternative and effective drugs. Synthetic derivatives of [(5-nitroieroaryl-2-yl) methylidene] hydrazineyl heteroaryl showed in vitro anti-plasmodial activity. The aim of this study was to evaluate the molecular binding and antiplasmid activity of in vivo synthetic compounds.Methods: The molecular docking was used to study the binding of compounds to heme and Plasmodium falciparum lactate dehydrogenase (PfLDH). Acute toxicity of the synthetic compounds was evaluated based on modified up & down method. Anti-plasmodial activity of the compounds was conducted by two standard methods of Peter and Rane’s tests via chloroquine-sensitive Plasmodium berghei . Also, the toxicity of mice’s internal organs was evaluated on day 7 in addition to the histopathology of their liver.Results The docking studies showed that active site of PfLDH had at least four common residues including Ala98, Ile54, Gly29 and Tyr97 to bind the compounds with the affinity ranging from -8.0 to -8.4 Kcal/mol. The mode of binding of ligands to heme revealed effective binding affinity ranging from -5.1 to -5.5 Kcal/mol. Compound 2 showed the highest % suppression of parasitemia (99.09%) at the dose of 125mg/kg/day in Peter’s tests. Compound 3 with 79.42% suppression was the best compounds in Rane’s test at the lowest dose (31.25 mg/kg/day). The histopathology of the mice’s livers did not reveal the focal necrosis of hepatocytes in the studied compounds.Conclusions The docking studies verified Pf LDH inhibition and the inhibitory effect on the hemozoin formation for the studied compounds. Accordingly, some compounds may provide new achievements for the development of antimalarial drugs without liver toxicity, although further studies are required to optimize their anti-plasmodial activity.

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Insight into molecular interactions of Aβ peptide and gelatinase from Enterococcus faecalis: a molecular modeling approach

Abstract: Alzheimer's disease is characterized by the presence of extracellular deposition of amyloid beta (Aβ) peptides.

Cited by 22 publications

References 87 publications

Molecular insights into Aβ₄₂ protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study

Molecular insights into Aβ₄₂ protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study

Molecular modeling studies to explore the binding affinity of virtually screened inhibitor toward different aminoglycoside kinases from diverse MDR strains

In silico and in vivo anti-malarial investigation on [(5-nitroheteroaryl-2-yl) methylidene] hydrazinyl hetroaryl derivatives

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Insight into molecular interactions of Aβ peptide and gelatinase from Enterococcus faecalis: a molecular modeling approach

Abstract: Alzheimer's disease is characterized by the presence of extracellular deposition of amyloid beta (Aβ) peptides.

Cited by 22 publications

References 87 publications

Molecular insights into Aβ42 protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study

Molecular insights into Aβ42 protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study

Molecular modeling studies to explore the binding affinity of virtually screened inhibitor toward different aminoglycoside kinases from diverse MDR strains

In silico and in vivo anti-malarial investigation on [(5-nitroheteroaryl-2-yl) methylidene] hydrazinyl hetroaryl derivatives

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Molecular insights into Aβ₄₂ protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study

Molecular insights into Aβ₄₂ protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study