scholarly journals Study of Caspase 8 Inhibition for the Management of Alzheimer’s Disease: A Molecular Docking and Dynamics Simulation

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2071
Author(s):  
Syed Sayeed Ahmad ◽  
Meetali Sinha ◽  
Khurshid Ahmad ◽  
Mohammad Khalid ◽  
Inho Choi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Md Simulation ◽  
Simulation Analysis ◽  
Dynamics Simulation ◽  
Caspase 8 ◽  
Amino Acid Residues ◽  
The Stability ◽  
Molecular Docking And Dynamics

Alzheimer’s disease (AD) is the most common type of dementia and usually manifests as diminished episodic memory and cognitive functions. Caspases are crucial mediators of neuronal death in a number of neurodegenerative diseases, and caspase 8 is considered a major therapeutic target in the context of AD. In the present study, we performed a virtual screening of 200 natural compounds by molecular docking with respect to their abilities to bind with caspase 8. Among them, rutaecarpine was found to have the highest (negative) binding energy (−6.5 kcal/mol) and was further subjected to molecular dynamics (MD) simulation analysis. Caspase 8 was determined to interact with rutaecarpine through five amino acid residues, specifically Thr337, Lys353, Val354, Phe355, and Phe356, and two hydrogen bonds (ligand: H35-A: LYS353:O and A:PHE355: N-ligand: N5). Furthermore, a 50 ns MD simulation was conducted to optimize the interaction, to predict complex flexibility, and to investigate the stability of the caspase 8–rutaecarpine complex, which appeared to be quite stable. The obtained results propose that rutaecarpine could be a lead compound that bears remarkable anti-Alzheimer’s potential against caspase 8.

scholarly journals Genes Identification, Molecular Docking and Dynamics Simulation Analysis of Laccases from Amylostereum areolatum Provides Molecular Basis of Laccase Bound to Lignin

2020 ◽  
Vol 21 (22) ◽  
pp. 8845
Author(s):  
Ningning Fu ◽  
Jiaxing Li ◽  
Ming Wang ◽  
Lili Ren ◽  
Youqing Luo
Keyword(s):  
Molecular Docking ◽  
Molecular Basis ◽  
Simulation Analysis ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Amino Acid Residues ◽  
Sirex Noctilio ◽  
Mutualistic Relationship ◽  
Laccase Genes ◽  
Molecular Docking And Dynamics

An obligate mutualistic relationship exists between the fungus Amylostereum areolatum and woodwasp Sirex noctilio. The fungus digests lignin in the host pine, providing essential nutrients for the growing woodwasp larvae. However, the functional properties of this symbiosis are poorly described. In this study, we identified, cloned, and characterized 14 laccase genes from A. areolatum. These genes encoded proteins of 508 to 529 amino acids and contained three typical copper-oxidase domains, necessary to confer laccase activity. Besides, we performed molecular docking and dynamics simulation of the laccase proteins in complex with lignin compounds (monomers, dimers, trimers, and tetramers). AaLac2, AaLac3, AaLac6, AaLac8, and AaLac10 were found that had low binding energies with all lignin model compounds tested and three of them could maintain stability when binding to these compounds. Among these complexes, amino acid residues ALA, GLN, LEU, PHE, PRO, and SER were commonly present. Our study reveals the molecular basis of A. areolatum laccases interacting with lignin, which is essential for understanding how the fungus provides nutrients to S. noctilio. These findings might also provide guidance for the control of S. noctilio by informing the design of enzyme mutants that could reduce the efficiency of lignin degradation.

scholarly journals Molecular Docking and Dynamics Simulation Study of Hyrtios erectus Isolated Scalarane Sesterterpenes as Potential SARS-CoV-2 Dual Target Inhibitors

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 389
Author(s):  
Sameh S. Elhady ◽  
Reda F. A. Abdelhameed ◽  
Rania T. Malatani ◽  
Abdulrahman M. Alahdal ◽  
Hanin A. Bogari ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Md Simulation ◽  
Protein Complexes ◽  
Antiviral Agents ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Main Protease ◽  
Simulation Parameters ◽  
Molecular Docking And Dynamics ◽  
Dual Target

Presently, the world is under the toll of pandemic coronavirus disease-2019 (COVID-19) outbreak caused by SARS-CoV-2. Lack of effective and safe therapeutics has stressed the scientific community for developing novel therapeutics capable of alleviating and stopping this pandemic. Within the presented study, molecular docking, ADME properties and all-atom molecular dynamic (MD) simulation, along with two standard antiviral agents (lopinavir and benzopurpurin-4B), were applied to investigate 15 scalaranes sesterterpenes natural compounds, purified from the Red Sea marine sponge Hyrtios erectus, as potential COVID-19 dual-target inhibitors. Following multi-step docking within COVID-19 main protease and Nsp15 endoribonuclease cavities, nine promising drug-like compounds exhibited higher docking scores as well as better interactions with the target’s crucial residues than those of reference ligands. Compounds 2, 6, 11, and 15, were predicted to simultaneously subdue the activity of the two COVID-19 targets. Dynamics behavior of the best-docked molecules, compounds 15 and 6, within COVID-19 target pockets showed substantial stability of ligand-protein complexes as presented via several MD simulation parameters. Furthermore, calculated free-binding energies from MD simulation illustrated significant ligand’s binding affinity towards respective target pockets. All provided findings supported the utility of scalarane-based sesterterpenes, particularly compounds 15 and 6, as promising lead candidates guiding the development of effective therapeutics against SARS-CoV-2.

scholarly journals Effect of Lauric Acid on the Stability of Aβ42-Oligomers

2020 ◽  
Author(s):  
Prabir Khatua ◽  
Asis Jana ◽  
Ulrich H. E. Hansmann
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Molecular Dynamics Simulation ◽  
Lauric Acid ◽  
Cell Membranes ◽  
Dynamics Simulation ◽  
The Stability

AbstractWhile Alzheimer’s disease is correlated with the presence of Aβ fibrils in patient brains, the more likely agents are their precursors, soluble oligomers that may form pores or otherwise distort cell membranes. Using all-atom molecular dynamics simulation we study how presence of fatty acids such as lauric acid changes the stability of pore-forming oligomers built from three-stranded Aβ42 chains. Such a change would alter the distribution of amyloids in the fatty-acid rich brain environment, and therefore could explain the lower polymorphism observed in Aβ-fibrils derived from brains of patients with Alzheimer’s disease. We find that lauric acid stabilizes both ring-like and barrel-shaped models, with the effect being stronger for barrel-like models than for ring-like oligomers.

scholarly journals Computational Exploration of Phytochemicals as Potent Inhibitors of Acetylcholinesterase Enzyme in Alzheimer’s Disease

2020 ◽  
Author(s):  
Bishajit Sarkar ◽  
Md. Asad Ullah ◽  
Md. Nazmul Islam Prottoy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
Docking Study ◽  
Dynamics Simulation ◽  
Normal Brain ◽  
Molecular Docking Study ◽  
Brain Functions ◽  
Age Related ◽  
Acetylcholinesterase Enzyme

AbstractAlzheimer’s Disease (AD) is the most common type of age related dementia in the world. Many hypotheses shed light on several reasons that lead to AD development. The cholinergic hypothesis describes that the destruction of an essential neurotransmitter, acetylcholine (AChE) by acetylcholinesterase (AChE) enzyme, leads to the AD onset. The hydrolysis of acetylcholine by excess amount of AChE decreases the amount of acetylcholine in the brain, thus interfering with the normal brain functions. Many anti-AChE agents can be used to treat AD by targeting AChE. In our study, 14 anti-AChE agents from plants: 1,8-cineol, berberine, carvacrol, cheilanthifoline, coptisine, estragole, harmaline, harmine, liriodenine, myrtenal, naringenin, protopine, scoulerine, stylopine were tested against AChE and compared with two controls: donepezil and galantamine, using different techniques of molecular docking. Molecular docking study was conducted for all the 14 selected ligands against AChE to identify the best three ligands among them. To determine the safety and efficacy of the three best ligands, a set of tests like the druglikeness property test, ADME/T test, PASS & P450 site of metabolism prediction, pharmacophore mapping and modelling and DFT calculations were performed. In our experiment, berberine, coptisine and naringenin were determined as the three ligands from the docking study. Further analysis of these 3 ligands showed coptisine as the most potent anti-AChE agent. The molecular dynamics simulation study showed quite good stability of the coptisine-AChE docked complex. Administration of berberine, coptisine and naringenin might be potential treatments for AD.

Molecular docking, molecular dynamics simulation, and ADMET analysis of levamisole derivatives against the SARS-CoV-2 main protease (MPro)

Bioimpacts ◽  
2021 ◽  
Author(s):  
Khalil EL Khatabi ◽  
Ilham Aanouz ◽  
Marwa Alaqarbeh ◽  
Mohammed Aziz Ajana ◽  
Tahar Lakhlifi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Md Simulation ◽  
Antiviral Agents ◽  
Dynamics Simulation ◽  
Main Protease ◽  
In Silico Admet ◽  
Wet Lab ◽  
The Stability ◽  
Drug Leads

Introduction: The new species of coronaviruses (CoVs), SARS-CoV-2, was reported as responsible for an outbreak of respiratory disease. Scientists and researchers are endeavoring to develop new approaches for the effective treatment against of the COVID-19 disease. There are no finally targeted antiviral agents able to inhibit the SARS-CoV-2 at present. Therefore, it is of interest to investigate the potential uses of levamisole derivatives, which are reported to be antiviral agents targeting the influenza virus. Methods: In the present study, 12 selected levamisole derivatives containing imidazo[2,1-b]thiazole were subjected to molecular docking in order to explore the binding mechanisms between these derivatives and the SARS-CoV-2 Mpro (PDB: 7BQY). The levamisole derivatives were evaluated for in silico ADMET properties for wet-lab applicability. Further, the stability of the best-docked complex was checked using molecular dynamics (MD) simulation at 20 ns. Results: Levamisole derivatives and especially molecule N°6 showed more promising docking results, presenting favorable binding interactions as well as better docking energy compared to chloroquine and mefloquine. The results of ADMET prediction and MD simulation support the potential of the molecule N°6 to be further developed as a novel inhibitor able to stop the newly emerged SARS-CoV-2. Conclusion: This research provided an effective first line in the rapid discovery of drug leads against the novel CoV (SARS-CoV-2).

scholarly journals Insight Into Seeded Tau Fibril Growth From Molecular Dynamics Simulation of the Alzheimer’s Disease Protofibril Core

2021 ◽  
Vol 8 ◽  
Author(s):  
Cass Leonard ◽  
Christian Phillips ◽  
James McCarty
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Free Energy ◽  
Energy Surface ◽  
Dynamics Simulation ◽  
Major Constituent ◽  
Dissociation Pathway ◽  
Free Energy Surface ◽  
The Stability

Aggregates of the microtubule associated tau protein are a major constituent of neurofibrillary lesions that define Alzheimer’s disease (AD) pathology. Increasing experimental evidence suggests that the spread of tau neurofibrillary tangles results from a prion-like seeding mechanism in which small oligomeric tau fibrils template the conversion of native, intrinsically disordered, tau proteins into their pathological form. By using atomistic molecular dynamics (MD) simulations, we investigate the stability and dissociation thermodynamics of high-resolution cryo-electron microscopy (cryo-EM) structures of both the AD paired-helical filament (PHF) and straight filament (SF). Non-equilibrium steered MD (SMD) center-of-mass pulling simulations are used to probe the stability of the protofibril structure and identify intermolecular contacts that must be broken before a single tau peptide can dissociate from the protofibril end. Using a combination of exploratory metadynamics and umbrella sampling, we investigate the complete dissociation pathway and compute a free energy profile for the dissociation of a single tau peptide from the fibril end. Different features of the free energy surface between the PHF and SF protofibril result from a different mechanism of tau unfolding. Comparison of wild-type tau PHF and post-translationally modified pSer356 tau shows that phosphorylation at this site changes the dissociation free energy surface of the terminal peptide. These results demonstrate how different protofibril morphologies template the folding of endogenous tau in distinct ways, and how post-translational modification can perturb the folding mechanism.

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