scholarly journals Identification of Compounds for Butyrylcholinesterase Inhibition

2021 ◽  
pp. 247255522110308
Author(s):  
Shuaizhang Li ◽  
Andrew J. Li ◽  
Jameson Travers ◽  
Tuan Xu ◽  
Srilatha Sakamuru ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Active Sites ◽  
Critical Role ◽  
Binding Modes ◽  
Inhibition Assay ◽  
Ache Inhibition ◽  
Primary Screening ◽  
Nnc 756 ◽  
Large Compound ◽  
Structural Classes

Butyrylcholinesterase (BChE) is a nonspecific cholinesterase enzyme that hydrolyzes choline-based esters. BChE plays a critical role in maintaining normal cholinergic function like acetylcholinesterase (AChE) through hydrolyzing acetylcholine (ACh). Selective BChE inhibition has been regarded as a viable therapeutic approach in Alzheimer’s disease. As of now, a limited number of selective BChE inhibitors are available. To identify BChE inhibitors rapidly and efficiently, we have screened 8998 compounds from several annotated libraries against an enzyme-based BChE inhibition assay in a quantitative high-throughput screening (qHTS) format. From the primary screening, we identified a group of 125 compounds that were further confirmed to inhibit BChE activity, including previously reported BChE inhibitors (e.g., bambuterol and rivastigmine) and potential novel BChE inhibitors (e.g., pancuronium bromide and NNC 756), representing diverse structural classes. These BChE inhibitors were also tested for their selectivity by comparing their IC50 values in BChE and AChE inhibition assays. The binding modes of these compounds were further studied using molecular docking analyses to identify the differences between the interactions of these BChE inhibitors within the active sites of AChE and BChE. Our qHTS approach allowed us to establish a robust and reliable process to screen large compound collections for potential BChE inhibitors.

On the Adsorption of Aspartate Derivatives to Calcite Surfaces in Aqueous Environment

2020 ◽  
Author(s):  
Robert Stepic ◽  
Lara Jurković ◽  
Ksenia Klementyeva ◽  
Marko Ukrainczyk ◽  
Matija Gredičak ◽  
...  
Keyword(s):  
Active Sites ◽  
Realistic Model ◽  
Binding Energies ◽  
Inhibition Mechanism ◽  
Aqueous Environment ◽  
Binding Modes ◽  
Carboxylate Groups ◽  
Dissolved Ions ◽  
Living Organisms ◽  
Dynamics Simulations

In many living organisms, biomolecules interact favorably with various surfaces of calcium carbonate. In this work, we have considered the interactions of aspartate (Asp) derivatives, as models of complex biomolecules, with calcite. Using kinetic growth experiments, we have investigated the inhibition of calcite growth by Asp, Asp2 and Asp3.This entailed the determination of a step-pinning growth regime as well as the evaluation of the adsorption constants and binding free energies for the three species to calcite crystals. These latter values are compared to free energy profiles obtained from fully atomistic molecular dynamics simulations. When using a flat (104) calcite surface in the models, the measured trend of binding energies is poorly reproduced. However, a more realistic model comprised of a surface with an island containing edges and corners, yields binding energies that compare very well with experiments. Surprisingly, we find that most binding modes involve the positively charged, ammonium group. Moreover, while attachment of the negatively charged carboxylate groups is also frequently observed, it is always balanced by the aqueous solvation of an equal or greater number of carboxylates. These effects are observed on all calcite features including edges and corners, the latter being associated with dominant affinities to Asp derivatives. As these features are also precisely the active sites for crystal growth, the experimental and theoretical results point strongly to a growth inhibition mechanism whereby these sites become blocked, preventing further attachment of dissolved ions and halting further growth.

Exploring Proteomic Drug Targets, Therapeutic Strategies and Protein - Protein Interactions in Cancer: Mechanistic View

2019 ◽  
Vol 19 (6) ◽  
pp. 430-448 ◽  
Author(s):  
Khalid Bashir Dar ◽  
Aashiq Hussain Bhat ◽  
Shajrul Amin ◽  
Syed Anjum ◽  
Bilal Ahmad Reshi ◽  
...  
Keyword(s):  
Protein Interactions ◽  
High Throughput Screening ◽  
Critical Role ◽  
Cancer Therapeutics ◽  
Adaptor Proteins ◽  
Therapeutic Strategies ◽  
Small Gtpases ◽  
Beta Catenin ◽  
Protein Protein Interactions ◽  
Apoptosis Protein

Protein-Protein Interactions (PPIs) drive major signalling cascades and play critical role in cell proliferation, apoptosis, angiogenesis and trafficking. Deregulated PPIs are implicated in multiple malignancies and represent the critical targets for treating cancer. Herein, we discuss the key protein-protein interacting domains implicated in cancer notably PDZ, SH2, SH3, LIM, PTB, SAM and PH. These domains are present in numerous enzymes/kinases, growth factors, transcription factors, adaptor proteins, receptors and scaffolding proteins and thus represent essential sites for targeting cancer. This review explores the candidature of various proteins involved in cellular trafficking (small GTPases, molecular motors, matrix-degrading enzymes, integrin), transcription (p53, cMyc), signalling (membrane receptor proteins), angiogenesis (VEGFs) and apoptosis (BCL-2family), which could possibly serve as targets for developing effective anti-cancer regimen. Interactions between Ras/Raf; X-linked inhibitor of apoptosis protein (XIAP)/second mitochondria-derived activator of caspases (Smac/DIABLO); Frizzled (FRZ)/Dishevelled (DVL) protein; beta-catenin/T Cell Factor (TCF) have also been studied as prospective anticancer targets. Efficacy of diverse molecules/ drugs targeting such PPIs although evaluated in various animal models/cell lines, there is an essential need for human-based clinical trials. Therapeutic strategies like the use of biologicals, high throughput screening (HTS) and fragment-based technology could play an imperative role in designing cancer therapeutics. Moreover, bioinformatic/computational strategies based on genome sequence, protein sequence/structure and domain data could serve as competent tools for predicting PPIs. Exploring hot spots in proteomic networks represents another approach for developing targetspecific therapeutics. Overall, this review lays emphasis on a productive amalgamation of proteomics, genomics, biochemistry, and molecular dynamics for successful treatment of cancer.

scholarly journals Hydrogen production from water electrolysis: role of catalysts

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Shan Wang ◽  
Aolin Lu ◽  
Chuan-Jian Zhong
Keyword(s):  
Hydrogen Production ◽  
Water Splitting ◽  
Noble Metal ◽  
Active Sites ◽  
Current Knowledge ◽  
Low Cost ◽  
Critical Role ◽  
Water Electrolysis ◽  
Efficient Production ◽  
Production Of Hydrogen

AbstractAs a promising substitute for fossil fuels, hydrogen has emerged as a clean and renewable energy. A key challenge is the efficient production of hydrogen to meet the commercial-scale demand of hydrogen. Water splitting electrolysis is a promising pathway to achieve the efficient hydrogen production in terms of energy conversion and storage in which catalysis or electrocatalysis plays a critical role. The development of active, stable, and low-cost catalysts or electrocatalysts is an essential prerequisite for achieving the desired electrocatalytic hydrogen production from water splitting for practical use, which constitutes the central focus of this review. It will start with an introduction of the water splitting performance evaluation of various electrocatalysts in terms of activity, stability, and efficiency. This will be followed by outlining current knowledge on the two half-cell reactions, hydrogen evolution reaction (HER) and oxygen evolution reaction (OER), in terms of reaction mechanisms in alkaline and acidic media. Recent advances in the design and preparation of nanostructured noble-metal and non-noble metal-based electrocatalysts will be discussed. New strategies and insights in exploring the synergistic structure, morphology, composition, and active sites of the nanostructured electrocatalysts for increasing the electrocatalytic activity and stability in HER and OER will be highlighted. Finally, future challenges and perspectives in the design of active and robust electrocatalysts for HER and OER towards efficient production of hydrogen from water splitting electrolysis will also be outlined.

scholarly journals Catalytic activity and stereoselectivity of engineered phosphotriesterases towards structurally different nerve agents in vitro

2021 ◽  
Author(s):  
Anja Köhler ◽  
Benjamin Escher ◽  
Laura Job ◽  
Marianne Koller ◽  
Horst Thiermann ◽  
...  
Keyword(s):  
Plasma Clearance ◽  
Nerve Agents ◽  
Inhibition Assay ◽  
Ache Inhibition ◽  
Catalytic Activities ◽  
Chiral Lc ◽  
Hydrolysis Of ◽  
Medical Countermeasures

AbstractHighly toxic organophosphorus nerve agents, especially the extremely stable and persistent V-type agents such as VX, still pose a threat to the human population and require effective medical countermeasures. Engineered mutants of the Brevundimonas diminuta phosphotriesterase (BdPTE) exhibit enhanced catalytic activities and have demonstrated detoxification in animal models, however, substrate specificity and fast plasma clearance limit their medical applicability. To allow better assessment of their substrate profiles, we have thoroughly investigated the catalytic efficacies of five BdPTE mutants with 17 different nerve agents using an AChE inhibition assay. In addition, we studied one BdPTE version that was fused with structurally disordered PAS polypeptides to enable delayed plasma clearance and one bispecific BdPTE with broadened substrate spectrum composed of two functionally distinct subunits connected by a PAS linker. Measured kcat/KM values were as high as 6.5 and 1.5 × 108 M−1 min−1 with G- and V-agents, respectively. Furthermore, the stereoselective degradation of VX enantiomers by the PASylated BdPTE-4 and the bispecific BdPTE-7 were investigated by chiral LC–MS/MS, resulting in a several fold faster hydrolysis of the more toxic P(−) VX stereoisomer compared to P(+) VX. In conclusion, the newly developed enzymes BdPTE-4 and BdPTE-7 have shown high catalytic efficacy towards structurally different nerve agents and stereoselectivity towards the toxic P(−) VX enantiomer in vitro and offer promise for use as bioscavengers in vivo.

scholarly journals Searching novel complex solid solution electrocatalysts in unconventional element combinations

Nano Research ◽  
2021 ◽  
Author(s):  
Olga A. Krysiak ◽  
Simon Schumacher ◽  
Alan Savan ◽  
Wolfgang Schuhmann ◽  
Alfred Ludwig ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Active Sites ◽  
Search Space ◽  
Reduction Reaction ◽  
Film Material ◽  
X Ray ◽  
High Entropy ◽  
Catalyst Composition ◽  
Scanning Transmission

AbstractDespite outstanding accomplishments in catalyst discovery, finding new, more efficient, environmentally neutral, and noble metal-free catalysts remains challenging and unsolved. Recently, complex solid solutions consisting of at least five different elements and often named as high-entropy alloys have emerged as a new class of electrocatalysts for a variety of reactions. The multicomponent combinations of elements facilitate tuning of active sites and catalytic properties. Predicting optimal catalyst composition remains difficult, making testing of a very high number of them indispensable. We present the high-throughput screening of the electrochemical activity of thin film material libraries prepared by combinatorial co-sputtering of metals which are commonly used in catalysis (Pd, Cu, Ni) combined with metals which are not commonly used in catalysis (Ti, Hf, Zr). Introducing unusual elements in the search space allows discovery of catalytic activity for hitherto unknown compositions. Material libraries with very similar composition spreads can show different activities vs. composition trends for different reactions. In order to address the inherent challenge of the huge combinatorial material space and the inability to predict active electrocatalyst compositions, we developed a high-throughput process based on co-sputtered material libraries, and performed high-throughput characterization using energy dispersive X-ray spectroscopy (EDS), scanning transmission electron microscopy (SEM), X-ray diffraction (XRD) and conductivity measurements followed by electrochemical screening by means of a scanning droplet cell. The results show surprising material compositions with increased activity for the oxygen reduction reaction and the hydrogen evolution reaction. Such data are important input data for future data-driven materials prediction.

On the Nature of Grain Boundaries in Nanocrystalline Diamond

MRS Bulletin ◽  
1998 ◽  
Vol 23 (9) ◽  
pp. 36-41 ◽  
Author(s):  
P. Keblinski ◽  
D. Wolf ◽  
F. Cleri ◽  
S.R. Phillpot ◽  
H. Gleiter
Keyword(s):  
Grain Size ◽  
Grain Boundaries ◽  
Active Sites ◽  
Critical Role ◽  
Diamond Films ◽  
Structural Disorder ◽  
Nanocrystalline Diamond ◽  
High Wear Resistance ◽  
Atomic Structures ◽  
Nanocrystalline Diamond Films

The low-pressure synthesis of rather pure nanocrystalline diamond films from fullerene precursors suggests that for a small enough grain size the diamond structure may be energetically preferred over graphite. Because of the small grain size of typically about 15 nm in these films, a significant fraction of the carbon atoms is situated in the grain boundaries (GBs). The surprisingly high wear resistance of these films even after the substrate is removed and their high corrosion resistance suggest that the grains are strongly bonded. Grain-boundary carbon is also believed to be responsible for the absorption and scattering of light in these films, for their electrical conductivity, and for their electron-emission properties. In spite of all these indications of a critical role played by GB carbon in achieving the remarkable properties of nanocrystalline diamond films, to date the atomic structures of the GBs are essentially not known.It is well-known that the electronic and optical properties of polycrystalline silicon films are significantly affected by the presence of GBs. For example GBs can provide active sites for the recombination of electron-hole pairs in photovoltaic applications. Also, in electronic devices such as thin-film transistors, GBs are known to play an important role. Because of silicon's strong energetic preference for sp3 hybridization over other electronic configurations, the structural disorder in silicon GBs is accommodated by a distortion of the tetrahedral nearestneighbor bonds and in the extreme by the creation of dangling bonds—that is, of three-coordinated Si atoms each having one unsaturated, bound electron in an otherwise more or less tetrahedrally coordinated environment.

Determination of the GH3.12 protein conformation through HPLC-integrated SAXS measurements combined with X-ray crystallography

2013 ◽  
Vol 69 (10) ◽  
pp. 2072-2080 ◽  
Author(s):  
Adam Round ◽  
Elizabeth Brown ◽  
Romain Marcellin ◽  
Ulrike Kapp ◽  
Corey S. Westfall ◽  
...  
Keyword(s):  
Protein Conformation ◽  
Active Sites ◽  
Solution Structure ◽  
Critical Role ◽  
X Ray ◽  
Hplc Purification ◽  
Closed Conformation ◽  
Terminal Domain ◽  
Redundant Data ◽  
On Line

The combination of protein crystallography and small-angle X-ray scattering (SAXS) provides a powerful method to investigate changes in protein conformation. These complementary structural techniques were used to probe the solution structure of the apo and the ligand-bound forms of theArabidopsis thalianaacyl acid–amido synthetase GH3.12. This enzyme is part of the extensive GH3 family and plays a critical role in the regulation of plant hormones through the formation of amino-acid-conjugated hormone productsviaan ATP-dependent reaction mechanism. The enzyme adopts two distinct C-terminal domain orientations with `open' and `closed' active sites. Previous studies suggested that ATP only binds in the open orientation. Here, the X-ray crystal structure of GH3.12 is presented in the closed conformation in complex with the nonhydrolysable ATP analogue AMPCPP and the substrate salicylate. Using on-line HPLC purification combined with SAXS measurements, the most likely apo and ATP-bound protein conformations in solution were determined. These studies demonstrate that the C-terminal domain is flexible in the apo form and favours the closed conformation upon ATP binding. In addition, these data illustrate the efficacy of on-line HPLC purification integrated into the SAXS sample-handling environment to reliably monitor small changes in protein conformation through the collection of aggregate-free and highly redundant data.

scholarly journals Computational Insight into Protein Tyrosine Phosphatase 1B Inhibition: A Case Study of the Combined Ligand- and Structure-Based Approach

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Xiangyu Zhang ◽  
Hailun Jiang ◽  
Wei Li ◽  
Jian Wang ◽  
Maosheng Cheng
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Active Sites ◽  
Tyrosine Phosphatase ◽  
Pharmacophore Model ◽  
Protein Tyrosine Phosphatase 1B ◽  
Binding Modes ◽  
Protein Tyrosine ◽  
R Region ◽  
Ptp1b Inhibitors ◽  
Autodock 4.0

Protein tyrosine phosphatase 1B (PTP1B) is an attractive target for treating cancer, obesity, and type 2 diabetes. In our work, the way of combined ligand- and structure-based approach was applied to analyze the characteristics of PTP1B enzyme and its interaction with competitive inhibitors. Firstly, the pharmacophore model of PTP1B inhibitors was built based on the common feature of sixteen compounds. It was found that the pharmacophore model consisted of five chemical features: one aromatic ring (R) region, two hydrophobic (H) groups, and two hydrogen bond acceptors (A). To further elucidate the binding modes of these inhibitors with PTP1B active sites, four docking programs (AutoDock 4.0, AutoDock Vina 1.0, standard precision (SP) Glide 9.7, and extra precision (XP) Glide 9.7) were used. The characteristics of the active sites were then described by the conformations of the docking results. In conclusion, a combination of various pharmacophore features and the integration information of structure activity relationship (SAR) can be used to design novel potent PTP1B inhibitors.

scholarly journals Distinct histone H3–H4 binding modes of sNASP reveal the basis for cooperation and competition of histone chaperones

2021 ◽  
Author(s):  
Chao-Pei Liu ◽  
Wenxing Jin ◽  
Jie Hu ◽  
Mingzhu Wang ◽  
Jingjing Chen ◽  
...  
Keyword(s):  
De Novo ◽  
Critical Role ◽  
Histone H3 ◽  
Coiled Coil ◽  
Dynamic Network ◽  
Histone Chaperones ◽  
Binding Modes ◽  
Nucleosome Assembly ◽  
Partially Unfolded

Chromosomal duplication requires de novo assembly of nucleosomes from newly synthesized histones, and the process involves a dynamic network of interactions between histones and histone chaperones. sNASP and ASF1 are two major histone H3–H4 chaperones found in distinct and common complexes, yet how sNASP binds H3–H4 in the presence and absence of ASF1 remains unclear. Here we show that, in the presence of ASF1, sNASP principally recognizes a partially unfolded Nα region of histone H3, and in the absence of ASF1, an additional sNASP binding site becomes available in the core domain of the H3–H4 complex. Our study also implicates a critical role of the C-terminal tail of H4 in the transfer of H3–H4 between sNASP and ASF1 and the coiled-coil domain of sNASP in nucleosome assembly. These findings provide mechanistic insights into coordinated histone binding and transfer by histone chaperones.

scholarly journals Identification of different oxygen species in oxide nanostructures with 17O solid-state NMR spectroscopy

2015 ◽  
Vol 1 (1) ◽  
pp. e1400133 ◽  
Author(s):  
Meng Wang ◽  
Xin-Ping Wu ◽  
Sujuan Zheng ◽  
Li Zhao ◽  
Lei Li ◽  
...  
Keyword(s):  
Active Sites ◽  
Density Functional ◽  
Strong Dependence ◽  
Critical Role ◽  
Oxygen Species ◽  
Structure Property ◽  
Diverse Range ◽  
Oxygen Ions ◽  
Surface Sites ◽  
Nanostructured Oxides

Nanostructured oxides find multiple uses in a diverse range of applications including catalysis, energy storage, and environmental management, their higher surface areas, and, in some cases, electronic properties resulting in different physical properties from their bulk counterparts. Developing structure-property relations for these materials requires a determination of surface and subsurface structure. Although microscopy plays a critical role owing to the fact that the volumes sampled by such techniques may not be representative of the whole sample, complementary characterization methods are urgently required. We develop a simple nuclear magnetic resonance (NMR) strategy to detect the first few layers of a nanomaterial, demonstrating the approach with technologically relevant ceria nanoparticles. We show that the 17O resonances arising from the first to third surface layer oxygen ions, hydroxyl sites, and oxygen species near vacancies can be distinguished from the oxygen ions in the bulk, with higher-frequency 17O chemical shifts being observed for the lower coordinated surface sites. H217O can be used to selectively enrich surface sites, allowing only these particular active sites to be monitored in a chemical process. 17O NMR spectra of thermally treated nanosized ceria clearly show how different oxygen species interconvert at elevated temperature. Density functional theory calculations confirm the assignments and reveal a strong dependence of chemical shift on the nature of the surface. These results open up new strategies for characterizing nanostructured oxides and their applications.

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