scholarly journals Novel C7-Substituted Coumarins as Selective Monoamine Oxidase Inhibitors: Discovery, Synthesis and Theoretical Simulation

Molecules ◽  
2019 ◽  
Vol 24 (21) ◽  
pp. 4003 ◽  
Author(s):  
Dong Wang ◽  
Ren-Yuan Hong ◽  
Mengyao Guo ◽  
Yi Liu ◽  
Nianhang Chen ◽  
...  

There is a continued need to develop new selective human monoamine oxidase (hMAO) inhibitors that could be beneficial for the treatment of neurological diseases. However, hMAOs are closely related with high sequence identity and structural similarity, which hinders the development of selective MAO inhibitors. “Three-Dimensional Biologically Relevant Spectrum (BRS-3D)” method developed by our group has demonstrated its effectiveness in subtype selectivity studies of receptor and enzyme ligands. Here, we report a series of novel C7-substituted coumarins, either synthesized or commercially purchased, which were identified as selective hMAO inhibitors. Most of the compounds demonstrated strong activities with IC50 values (half-inhibitory concentration) ranging from sub-micromolar to nanomolar. Compounds, FR1 and SP1, were identified as the most selective hMAO-A inhibitors, with IC50 values of 1.5 nM (selectivity index (SI) < −2.82) and 19 nM (SI < −2.42), respectively. FR4 and FR5 showed the most potent hMAO-B inhibitory activity, with IC50 of 18 nM and 15 nM (SI > 2.74 and SI > 2.82). Docking calculations and molecular dynamic simulations were performed to elucidate the selectivity preference and SAR profiles.

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Song-Bing He ◽  
Ben Hu ◽  
Zheng-Kun Kuang ◽  
Dong Wang ◽  
De-Xin Kong

An amendment to this paper has been published and can be accessed via a link at the top of the paper.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chaojian Chen ◽  
Manjesh Kumar Singh ◽  
Katrin Wunderlich ◽  
Sean Harvey ◽  
Colette J. Whitfield ◽  
...  

AbstractThe creation of synthetic polymer nanoobjects with well-defined hierarchical structures is important for a wide range of applications such as nanomaterial synthesis, catalysis, and therapeutics. Inspired by the programmability and precise three-dimensional architectures of biomolecules, here we demonstrate the strategy of fabricating controlled hierarchical structures through self-assembly of folded synthetic polymers. Linear poly(2-hydroxyethyl methacrylate) of different lengths are folded into cyclic polymers and their self-assembly into hierarchical structures is elucidated by various experimental techniques and molecular dynamics simulations. Based on their structural similarity, macrocyclic brush polymers with amphiphilic block side chains are synthesized, which can self-assemble into wormlike and higher-ordered structures. Our work points out the vital role of polymer folding in macromolecular self-assembly and establishes a versatile approach for constructing biomimetic hierarchical assemblies.


Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3896
Author(s):  
Geum Seok Jeong ◽  
Myung-Gyun Kang ◽  
Joon Yeop Lee ◽  
Sang Ryong Lee ◽  
Daeui Park ◽  
...  

Eight compounds were isolated from the roots of Glycyrrhiza uralensis and tested for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activities. The coumarin glycyrol (GC) effectively inhibited butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) with IC50 values of 7.22 and 14.77 µM, respectively, and also moderately inhibited MAO-B (29.48 µM). Six of the other seven compounds only weakly inhibited AChE and BChE, whereas liquiritin apioside moderately inhibited AChE (IC50 = 36.68 µM). Liquiritigenin (LG) potently inhibited MAO-B (IC50 = 0.098 µM) and MAO-A (IC50 = 0.27 µM), and liquiritin, a glycoside of LG, weakly inhibited MAO-B (>40 µM). GC was a reversible, noncompetitive inhibitor of BChE with a Ki value of 4.47 µM, and LG was a reversible competitive inhibitor of MAO-B with a Ki value of 0.024 µM. Docking simulations showed that the binding affinity of GC for BChE (−7.8 kcal/mol) was greater than its affinity for AChE (−7.1 kcal/mol), and suggested that GC interacted with BChE at Thr284 and Val288 by hydrogen bonds (distances: 2.42 and 1.92 Å, respectively) beyond the ligand binding site of BChE, but that GC did not form hydrogen bond with AChE. The binding affinity of LG for MAO-B (−8.8 kcal/mol) was greater than its affinity for MAO-A (−7.9 kcal/mol). These findings suggest GC and LG should be considered promising compounds for the treatment of Alzheimer’s disease with multi-targeting activities.


2014 ◽  
Vol 610 ◽  
pp. 425-428
Author(s):  
Wei Jian Liu ◽  
Si Da Xiao ◽  
Ruo He Yao

In this paper, we propose a new super-resolution algorithm based on wavelet coefficient. The proposed algorithm uses discrete wavelet transform (DWT) to decompose the input low-resolution image sequences into four subband images, including LL, LH, HL, HH. Then the input images have been processed by the 3DSKR (Three Dimensional Steering Kernel Regression) super resolution (SR) algorithm, and the result replaces the LL subband image, while the three high-frequency subband images have been interpolated. Finally, combining all these images to generate a new high-resolution image by using inverse DWT. Proposed method has been verified on Calendar and Foliage by Matlab software platform. The peak signal-to-noise (PSNR), structural similarity (SSIM) and visual results are compared, and show that the computational complexity of the proposed algorithm decline by 30 percent compared with the existing algorithm to obtain the approximate results.


2017 ◽  
Vol 149 (8) ◽  
pp. 799-811 ◽  
Author(s):  
Emre Lacin ◽  
Prafulla Aryal ◽  
Ian W. Glaaser ◽  
Karthik Bodhinathan ◽  
Eric Tsai ◽  
...  

G protein–gated inwardly rectifying potassium (GIRK) channels control neuronal excitability in the brain and are implicated in several different neurological diseases. The anionic phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2) is an essential cofactor for GIRK channel gating, but the precise mechanism by which PIP2 opens GIRK channels remains poorly understood. Previous structural studies have revealed several highly conserved, positively charged residues in the “tether helix” (C-linker) that interact with the negatively charged PIP2. However, these crystal structures of neuronal GIRK channels in complex with PIP2 provide only snapshots of PIP2’s interaction with the channel and thus lack details about the gating transitions triggered by PIP2 binding. Here, our functional studies reveal that one of these conserved basic residues in GIRK2, Lys200 (6′K), supports a complex and dynamic interaction with PIP2. When Lys200 is mutated to an uncharged amino acid, it activates the channel by enhancing the interaction with PIP2. Atomistic molecular dynamic simulations of neuronal GIRK2 with the same 6′ substitution reveal an open GIRK2 channel with PIP2 molecules adopting novel positions. This dynamic interaction with PIP2 may explain the intrinsic low open probability of GIRK channels and the mechanism underlying activation by G protein Gβγ subunits and ethanol.


Sensors ◽  
2018 ◽  
Vol 18 (11) ◽  
pp. 3852
Author(s):  
Lulu Wang

The authors recently developed a two-dimensional (2D) holographic electromagnetic induction imaging (HEI) for biomedical imaging applications. However, this method was unable to detect small inclusions accurately. For example, only one of two inclusions can be detected in the reconstructed image if the two inclusions were located at the same XY plane but in different Z-directions. This paper provides a theoretical framework of three-dimensional (3D) HEI to accurately and effectively detect inclusions embedded in a biological object. A numerical system, including a realistic head phantom, a 16-element excitation sensor array, a 16-element receiving sensor array, and image processing model has been developed to evaluate the effectiveness of the proposed method for detecting small stroke. The achieved 3D HEI images have been compared with 2D HEI images. Simulation results show that the 3D HEI method can accurately and effectively identify small inclusions even when two inclusions are located at the same XY plane but in different Z-directions. This preliminary study shows that the proposed method has the potential to develop a useful imaging tool for the diagnosis of neurological diseases and injuries in the future.


Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3047
Author(s):  
Luana C. Soares ◽  
Osama Al-Dalahmah ◽  
James Hillis ◽  
Christopher C. Young ◽  
Isaiah Asbed ◽  
...  

Galectin-3 (Gal-3) is an evolutionarily conserved and multifunctional protein that drives inflammation in disease. Gal-3′s role in the central nervous system has been less studied than in the immune system. However, recent studies show it exacerbates Alzheimer’s disease and is upregulated in a large variety of brain injuries, while loss of Gal-3 function can diminish symptoms of neurodegenerative diseases such as Alzheimer’s. Several novel molecular pathways for Gal-3 were recently uncovered. It is a natural ligand for TREM2 (triggering receptor expressed on myeloid cells), TLR4 (Toll-like receptor 4), and IR (insulin receptor). Gal-3 regulates a number of pathways including stimulation of bone morphogenetic protein (BMP) signaling and modulating Wnt signalling in a context-dependent manner. Gal-3 typically acts in pathology but is now known to affect subventricular zone (SVZ) neurogenesis and gliogenesis in the healthy brain. Despite its myriad interactors, Gal-3 has surprisingly specific and important functions in regulating SVZ neurogenesis in disease. Gal-1, a similar lectin often co-expressed with Gal-3, also has profound effects on brain pathology and adult neurogenesis. Remarkably, Gal-3′s carbohydrate recognition domain bears structural similarity to the SARS-CoV-2 virus spike protein necessary for cell entry. Gal-3 can be targeted pharmacologically and is a valid target for several diseases involving brain inflammation. The wealth of molecular pathways now known further suggest its modulation could be therapeutically useful.


2021 ◽  
Vol 4 (4(112)) ◽  
pp. 74-82
Author(s):  
Oksana Suprunenko

Paradigms and graphical-analytical tools for building simulation tools and forming the architecture of a combined approach to studying the dynamic properties of systems with parallelism are described. An extension of the formal language of Petri nets is presented, which has greater modeling power than WF nets. The properties of hierarchical Petri nets are used to synthesize a holistic model. Discrete-event modeling and modeling of dynamic systems, which allow reflecting the quantitative and qualitative characteristics of the elements of the systems under study, served as the basis for the combined approach to the simulation of systems with parallelism. On their basis, graphic-analytical tools are proposed that provide the ability to describe the modeled system, adhering to the principle of structural similarity. They have dynamic simulations that make it easy to visually analyze and correct the model. Also, the proposed toolkit provides for the analysis of the dynamic properties of the model, which makes it possible to identify accumulated phenomena that can lead to unpredictability of the system’s functioning. A conceptual model for the synthesis and analysis of systems with parallelism is proposed, which provides for the construction of the components of the model based on the architecture. Their step-by-step analysis and the formation of an integral model of the software system are carried out using a network representation, according to the matrix description of which invariants are calculated. The analysis of invariants allows one to obtain the dynamic properties of the model and determine the localization of structures that lead to critical situations when they are detected. The architecture of the combined approach to the simulation of systems with parallelism is built, which provides the study of their dynamic properties to improve the reliability of the functioning of software systems


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