Background: As the number of elderly persons increases, neurodegenerative diseases are
becoming ubiquitous. There is currently a great need for knowledge concerning management of oldage
...neurodegenerative diseases; the most important of which are: Alzheimer's disease, Parkinson's
disease, Amyotrophic Lateral Sclerosis, and Huntington’s disease.
Objective: To summarize the potential of computationally predicted molecules and targets against
neurodegenerative diseases.
Method: Review of literature published since 1997 against neurodegenerative diseases, utilizing as
keywords: in silico, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis ALS,
and Huntington's disease was conducted.
Results and Conclusion: Due to the costs associated with experimentation and current ethical law,
performing experiments directly on living organisms has become much more difficult. In this scenario,
in silico techniques have been successful and have become powerful tools in the search to
cure disease. Researchers use the Computer Aided Drug Design pipeline which: 1) generates 3-
dimensional structures of target proteins through homology modeling 2) achieves stabilization
through molecular dynamics simulation, and 3) exploits molecular docking through large compound
libraries. Next generation sequencing is continually producing enormous amounts of raw
sequence data while neuroimaging is producing a multitude of raw image data. To solve such pressing
problems, these new tools and algorithms are required. This review elaborates precise in silico
tools and techniques for drug targets, active molecules, and molecular docking studies, together
with future prospects and challenges concerning possible breakthroughs in Alzheimer's, Parkinson's,
Amyotrophic Lateral Sclerosis, and Huntington's disease.
Parkinson's disease (PD) is caused by loss in nigrostriatal dopaminergic neurons and is ranked as the second most common neurodegenerative disorder. Dopamine receptor D3 is considered as a potential ...target in drug development against PD because of its lesser side effects and higher degree of neuro-protection. One of the prominent therapies currently available for PD is the use of dopamine agonists which mimic the natural action of dopamine in the brain and stimulate dopamine receptors directly. Unfortunately, use of these pharmacological therapies such as bromocriptine, apomorphine, and ropinirole provides only temporary relief of the disease symptoms and is frequently linked with insomnia, anxiety, depression, and agitation. Thus, there is a need for an alternative treatment that not only hinders neurodegeneration, but also has few or no side effects. Since the past decade, much attention has been given to exploitation of phytochemicals and their use in alternative medicine research. This is because plants are a cheap, indispensable, and never ending resource of active compounds that are beneficial against various diseases. In the current study, 40 active phytochemicals against PD were selected through literature survey. These ligands were docked with dopamine receptor D3 using AutoDock and AutoDockVina. Binding energies were compared to docking results of drugs approved by the US Food and Drug Administration against PD. The compounds were further analyzed for their absorption, distribution, metabolism, and excretion-toxicity profile. From the study it is concluded that glycyrrhetinic acid and E.resveratroloside are potent compounds having high binding energies which should be considered as potential lead compounds for drug development against PD.
Wnt-4 (wingless mouse mammary tumor virus integration site-4) protein is involved in many crucial embryonic pathways regulating essential processes. Aberrant Wnt-4 activity causes various anomalies ...leading to gastric, colon, or breast cancer. Wnt-4 is a conserved protein in structure and sequence. All Wnt proteins contain an unusual fold comprising of a thumb (or N-terminal domain) and index finger (or C-terminal domain) bifurcated by a palm domain. The aim of this study was to identify the best inhibitors of Wnt-4 that not only interact with Wnt-4 protein but also with the covalently bound acyl group to inhibit aberrant Wnt-4 activity. A systematic computational approach was used to analyze inhibition of Wnt-4. Palmitoleic acid was docked into Wnt-4 protein, followed by ligand-based virtual screening of nearly 209,847 compounds; conformer generation of 271 compounds resulted from extensive virtual screening and comparative docking of 10,531 conformers of 271 unique compounds through GOLD (Genetic Optimization for Ligand Docking), AutoDock-Vina, and FRED (Fast Rigid Exhaustive Docking) was subsequently performed. Linux scripts was used to handle the libraries of compounds. The best compounds were selected on the basis of having maximum interactions to protein with bound palmitoleic acid. These represented lead inhibitors in further experiments. Palmitoleic acid is important for efficient Wnt activity, but aberrant Wnt-4 expression can be inhibited by designing inhibitors interacting with both protein and palmitoleic acid.
Wnt-4 is an important signaling protein of the Wnt family that acts in paracrine manner to a few cell diameters. Wnt-4 takes part in many developmental processes including sex determination, and ...kidney development and also plays role in brain as well. Wnt-4 has a total of 25 cysteine residues with conserved locations in relation to whole Wnt family. Due to unchallenged importance of Wnts and to study their unusual fold, Wnt-4 was considered for simulation to interpret and extract structural features dynamically. Comparative modeling approach was utilized to model Wnt-4 and minimized to remove any energy restraints. The minimized model was then subjected to molecular dynamics simulation with periodic boundary conditions, to understand its behavior in the presence of water-box. Wnt-4 behavior for 20-nanosecond (ns) simulation was analyzed by calculating the root mean square deviation (RMSD), root mean square fluctuation (RMSF), and b-factor. Prominently, twenty (20) cysteine residues were observed in the edges of loops participating in interactions with frizzled receptors. The higher values of RMSD with comparison to higher values of RMSF and b-factor of residues accompanying 20 cysteine residues lying in regions nearer to N- and C-terminal domains extrapolate that these residues might be involved in cysteine–cysteine disulfide linkages and are more important structurally and functionally as well.
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•Energy minimization•Structure validation•Molecular dynamics simulation•Connection of function and structural variability of the Wnt-4•Importance of thumb-index fold
Background As the number of elderly persons increases, neurodegenerative diseases are becoming ubiquitous. There is currently a great need for knowledge concerning management of old-age ...neurodegenerative diseases; the most important of which are: Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis, and Huntington’s disease. Objective To summarize the potential of computationally predicted molecules and targets against neurodegenerative diseases. Method Review of literature published since 1997 against neurodegenerative diseases, utilizing as keywords: in silico, Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis ALS, and Huntington’s disease was conducted. Results and Conclusion Due to the costs associated with experimentation and current ethical law, performing experiments directly on living organisms has become much more difficult. In this scenario, in silico techniques have been successful and have become powerful tools in the search to cure disease. Researchers use the Computer Aided Drug Design pipeline which: 1) generates 3-dimensional structures of target proteins through homology modeling 2) achieves stabilization through molecular dynamics simulation, and 3) exploits molecular docking through large compound libraries. Next generation sequencing is continually producing enormous amounts of raw sequence data while neuroimaging is producing a multitude of raw image data. To solve such pressing problems, these new tools and algorithms are required. This review elaborates precise in silico tools and techniques for drug targets, active molecules, and molecular docking studies, together with future prospects and challenges concerning possible breakthroughs in Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis, and Huntington’s disease.
Adiposomes are artificially prepared lipid droplet (LD)-mimetic structures, which, unlike LDs, do not harbor proteins. The dynamics of interaction between triacylglycerols (TAGs), drug molecule, and ...phospholipids in adiposomes is currently not well-established. Trioleoylglycerol (TOG) molecule was divided into three parts: two oleoyl tails and one 2-monooleoylglycerol (MOG). Forcefield parameters for two oleoyl tails were adopted from the AMBER18 repository while that of the MOG forcefield was taken from the literature. Charge correction was performed on the MOG forcefield before its utilization. After charge correction, the resulting TOG molecule had zero charge. TOG bilayer (2L) and tetralayer (4L) systems were prepared and simulated. TOG bilayer (2L) systems—modeled from two different initial conformations, the TOG3 conformation and the TOG2:1 conformation—showed that TOG2:1 conformation was more prevailing irrespective of the starting conformation and was subsequently used in further simulations. The hydrated TOG 2L system showed TOG–water solution solubility of 0.051 mol L−1 which is near experimental values. This validated the correct parameterization of the TOG molecule. The simulations of 4L systems showed stable membrane behaviors toward the end of simulations. It was also observed that in the 4L system, the TOG molecules showed the formation of micelles with the drug molecule. Almost six TOGs remained continuously in contact with the drug molecule throughout the simulation. The availability of charge-corrected TOG parameterization is expected to equip future studies with a framework for molecular dynamics simulations of adiposomes and/or LDs at the atomic level.
The world is experiencing a cancer epidemic and an increase in the prevalence of the disease. Cancer remains a major killer, accounting for more than half a million deaths annually. There is a wide ...range of natural products that have the potential to treat this disease. One of these products is artemisinin; a natural product from
Artemisia
plant. The Nobel Prize for Medicine was awarded in 2015 for the discovery of artemisinin in recognition of the drug’s efficacy. Artemisinin produces highly reactive free radicals by the breakdown of two oxygen atoms that kill cancerous cells. These cells sequester iron and accumulate as much as 1000 times in comparison with normal cells. Generally, chemotherapy is toxic to both cancerous cells and normal cells, while no significant cytotoxicity from artemisinin to normal cells has been found in more than 4000 case studies, which makes it far different than conventional chemotherapy. The pleiotropic response of artemisinin in cancer cells is responsible for growth inhibition by multiple ways including inhibition of angiogenesis, apoptosis, cell cycle arrest, disruption of cell migration, and modulation of nuclear receptor responsiveness. It is very encouraging that artemisinin and its derivatives are anticipated to be a novel class of broad-spectrum antitumor agents based on efficacy and safety. This review aims to highlight these achievements and propose potential strategies to develop artemisinin and its derivatives as a new class of cancer therapeutic agents.
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