Design,Synthesis, and Biological Evaluation of Novel Indanone Derivatives as Cholinesterase Inhibitors for Potential Use in Alzheimer's Disease

Indanone derivatives containing meta/para-substituted aminopropoxy benzyl/benzylidene moieties were designed based on the structures of donepezil and ebselen analogs as the cholinesterase inhibitors. The designed compounds were synthesized and their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities were measured. Inhibitory potencies (IC₅₀ values) for the synthesized compounds ranged from 0.12 to 11.92 μM and 0.04 to 24.36 μM against AChE and BChE, respectively. Compound 5 c showed the highest AChE inhibitory potency with IC₅₀ value of 0.12 μM, whereas the highest BChE inhibition was achieved by structure 7 b (IC₅₀=0.04 μM). Structure-activity relationship (SAR) analysis revealed that there is no significant difference between meta and para-substituted derivatives in AChE and BChE inhibition. However, the most potent AChE inhibitor 5 c belongs to meta-substituted compounds, while the most active BChE inhibitor is para-substituted derivative 7 b . The order of enzyme inhibition potency based on the substituted amine group is dimethyl amine>piperidine>morpholine. Compounds containing C=C linkage are more potent AChE inhibitors than the corresponding saturated structures. Molecular docking studies indicated that 5 c interacts with AChE in a very similar way to that observed experimentally for donepezil. The introduced indanone-aminopropoxy benzylidenes could be used in drug-discovery against Alzheimer's disease.     

Homology Modeling and Molecular Docking Studies of Glutamate Dehydrogenase (GDH) from Cyanobacterium Synechocystis sp. PCC 6803

Glutamate dehydrogenase (GDH), which is present in most bacteria and eukaryotes’ mitochondria, plays an important role in amino acid metabolism. In g     

Beam Manipulation by Hybrid Plasmonic-Dielectric Metasurfaces

A hybrid plasmonic-dielectric metasurface is proposed in order to manipulate beam propagation in desired manners. The metasurface is composed of patterned hybrid graphene-silicon nano-disks deposited on a low-index substrate, namely silica. It is shown that the proposed hybrid metasurface simultaneously benefits from the advantages of graphene-based metasurfaces and dielectric ones. Specially, we show that the proposed hybrid metasurface not only provides reconfigurability, just like previously proposed graphene-based metasurfaces, but also similar to dielectric metasurfaces, is of low loss and CMOS-compatible. Such exceptional features give the metasurface exceptional potentials to realize high efficient optical components. To demonstrate the latter point, focusing and anomalous reflection are performed making use of the proposed hybrid structure as examples of two well-known optical functionalities. This work opens up a new route in realization of reconfigurable meta-devices with widely real-world applications which cannot be achieved with their passive counterparts.

     

Utilization of the human gamma-satellite insulator for the enhancement of anti-PCSK9 monoclonal antibody expression in Chinese hamster ovary cells

Molecular Biology Reports - Monoclonal antibodies (mAbs) are widely employed as invaluable therapeutics for a vast number of human disorders. Several approaches have been introduced for the...     

Accounting for robustness in modeling signal transduction responses

Abstract

A classical question in systems biology is to find a Boolean model which is able to predict the observed responses of a signaling network. It has been previously shown that such models can be tailored based on experimental data. While fitting a minimum-size network to the experimentally observed data is a natural assumption, it can potentially result in a network which is not so robust against the noises in the training dataset. Indeed, it is widely accepted now that biological systems are generally evolved to be very robust. Therefore, in the present work, we extended the classical formulation of Boolean network construction in order to put weight on the robustness of the created network. We show that our method results generally in more relevant networks. Consequently, considering robustness as a design principle of biological networks can result in more realistic models.     

Dynamic Behavior of Rat Phosphoenolpyruvate Carboxykinase Inhibitors: New Mechanism for Enzyme Inhibition

As an enzyme acting at the junction of gluconeogenic pathway, phosphoenolpyruvate carboxykinase (PEPCK) controls substrate flow from Krebs cycle toward glucose production. Therefore, it would be advantageous to design effective inhibitors to inactivate PEPCK in diabetes mellitus and other abnormalities caused by insulin resistance. Such inhibitors may compensate the metabolic consequences of ex-activity of PEPCK at these conditions. Understanding the mechanism by which inhibitors exert their effect on enzyme activity is of great interest for designing stronger inhibitors. In the present work, molecular dynamic simulations were used to study enzyme-inhibitor interactions. Our results indicate that inhibitors of PEPCK with their short chains interact with enzyme active site through non-covalent interactions of electrostatic and hydrogen bond nature. The data also show that inhibitors neither reach a stable state in their binding site nor make static complex with the enzyme active site. Instead, they interact with functional groups of active site residues in a dynamic fashion. In this way, oxalate and sulfoacetate carrying two negative groups of higher charge density and optimum spacing from each other, show more dynamic behavior (lower stability in their binding site) and more inhibitory effects than other inhibitors used (phosphonoformate, phosphoglycolate and 3-phosphonopropionate).     

Urinary Metal Levels with Relation to Age,Occupation, and Smoking Habits of Male Inhabitants of Eastern Iran

Biological Trace Element Research - In low-income and middle-income countries such as Iran, smoking is becoming increasingly popular, especially among young people. This has led to additional...