scholarly journals Pick’s Tau Fibril Shows Multiple Distinct PET Probe Binding Sites: Insights from Computational Modelling

2020 ◽  
Vol 22 (1) ◽  
pp. 349
Author(s):  
Sushil K. Mishra ◽  
Yoshiki Yamaguchi ◽  
Makoto Higuchi ◽  
Naruhiko Sahara
Keyword(s):  
Binding Sites ◽  
Rational Design ◽  
Computational Modelling ◽  
Binding Energies ◽  
Pick's Disease ◽  
Pick’S Disease ◽  
Binding Modes ◽  
Surface Binding ◽  
Pet Tracers ◽  
Age Related

In recent years, it has been realized that the tau protein is a key player in multiple neurodegenerative diseases. Positron emission tomography (PET) radiotracers that bind to tau filaments in Alzheimer’s disease (AD) are in common use, but PET tracers binding to tau filaments of rarer, age-related dementias, such as Pick’s disease, have not been widely explored. To design disease-specific and tau-selective PET tracers, it is important to determine where and how PET tracers bind to tau filaments. In this paper, we present the first molecular modelling study on PET probe binding to the structured core of tau filaments from a patient with Pick’s disease (TauPiD). We have used docking, molecular dynamics simulations, binding-affinity and tunnel calculations to explore TauPiD binding sites, binding modes, and binding energies of PET probes (AV-1451, MK-6240, PBB3, PM-PBB3, THK-5351 and PiB) with TauPiD. The probes bind to TauPiD at multiple surface binding sites as well as in a cavity binding site. The probes show unique surface binding patterns, and, out of them all, PM-PBB3 proves to bind the strongest. The findings suggest that our computational workflow of structural and dynamic details of the tau filaments has potential for the rational design of TauPiD specific PET tracers.

scholarly journals Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607

2021 ◽  
Vol 141 (5) ◽  
pp. 697-708
Author(s):  
Yang Shi ◽  
Alexey G. Murzin ◽  
Benjamin Falcon ◽  
Alexander Epstein ◽  
Jonathan Machin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Binding Sites ◽  
Binding Activity ◽  
Cortical Atrophy ◽  
Binding Modes ◽  
Major Site ◽  
Age Related ◽  
Positron Emission

AbstractTau and Aβ assemblies of Alzheimer’s disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.

scholarly journals Designing multivalent probes for tunable superselective targeting

2015 ◽  
Vol 112 (18) ◽  
pp. 5579-5584 ◽  
Author(s):  
Galina V. Dubacheva ◽  
Tine Curk ◽  
Rachel Auzély-Velty ◽  
Daan Frenkel ◽  
Ralf P. Richter
Keyword(s):  
Binding Sites ◽  
Rational Design ◽  
Cell Surface Receptor ◽  
Molecular Characteristics ◽  
Surface Binding ◽  
Binding Properties ◽  
Practical Applications ◽  
Mechanistic Insight ◽  
Surface Receptor ◽  
Insight Into

Specific targeting is common in biology and is a key challenge in nanomedicine. It was recently demonstrated that multivalent probes can selectively target surfaces with a defined density of surface binding sites. Here we show, using a combination of experiments and simulations on multivalent polymers, that such “superselective” binding can be tuned through the design of the multivalent probe, to target a desired density of binding sites. We develop an analytical model that provides simple yet quantitative predictions to tune the polymer’s superselective binding properties by its molecular characteristics such as size, valency, and affinity. This work opens up a route toward the rational design of multivalent probes with defined superselective targeting properties for practical applications, and provides mechanistic insight into the regulation of multivalent interactions in biology. To illustrate this, we show how the superselective targeting of the extracellular matrix polysaccharide hyaluronan to its main cell surface receptor CD44 is controlled by the affinity of individual CD44–hyaluronan interactions.

scholarly journals Structure-Guided Computational Methods Predict Multiple Distinct Binding Modes for Pyrazoloquinolinones in GABAA Receptors

2021 ◽  
Vol 14 ◽  
Author(s):  
Jure Fabjan ◽  
Filip Koniuszewski ◽  
Benjamin Schaar ◽  
Margot Ernst
Keyword(s):  
Binding Sites ◽  
Rational Design ◽  
Transmembrane Domain ◽  
Complex Structure ◽  
Published Data ◽  
Receptor Subtypes ◽  
Binding Modes ◽  
Computational Docking ◽  
Structure Activity ◽  
Branching Points

Pyrazoloquinolinones (PQs) are a versatile class of GABAA receptor ligands. It has been demonstrated that high functional selectivity for certain receptor subtypes can be obtained by specific substitution patterns, but so far, no clear SAR rules emerge from the studies. As is the case for many GABAA receptor targeting chemotypes, PQs can interact with distinct binding sites on a given receptor pentamer. In pentamers of αβγ composition, such as the most abundant α1β2γ2 subtype, many PQs are high affinity binders of the benzodiazepine binding site at the extracellular α+/γ2− interfaces. There they display a functionally near silent, flumazenil-like allosteric activity. More recently, interactions with extracellular α+/β− interfaces have been investigated, where strong positive modulation can be steered toward interesting subtype preferences. The most prominent examples are functionally α6-selective PQs. Similar to benzodiazepines, PQs also seem to interact with sites in the transmembrane domain, mainly the sites used by etomidate and barbiturates. This promiscuity leads to potential contributions from multiple sites to net modulation. Developing ligands that interact exclusively with the extracellular α+/β− interfaces would be desired. Correlating functional profiles with binding sites usage is hampered by scarce and heterogeneous experimental data, as shown in our meta-analysis of aggregated published data. In the absence of experimental structures, bound states can be predicted with pharmacophore matching methods and with computational docking. We thus performed pharmacophore matching studies for the unwanted sites, and computational docking for the extracellular α1,6+/β3− interfaces. The results suggest that PQs interact with their binding sites with diverse binding modes. As such, rational design of improved ligands needs to take a complex structure-activity landscape with branches between sub-series of derivatives into account. We present a workflow, which is suitable to identify and explore potential branching points on the structure-activity landscape of any small molecule chemotype.

scholarly journals Adsorptive Removal of Arsenic by Synthetic Iron-loaded Goethite: Isotherms, Kinetics, and Mechanism

2021 ◽  
Author(s):  
Shakeel Ahmed Talpur ◽  
Muhammad Yousuf Jat Baloch ◽  
Chunli Su ◽  
Javed Iqbal ◽  
Aziz Ahmed
Keyword(s):  
Binding Sites ◽  
Arsenic Removal ◽  
Binding Energies ◽  
Coefficient Of Determination ◽  
Maximum Adsorption Capacity ◽  
Surface Binding ◽  
Arsenic Adsorption ◽  
Freundlich Isotherms ◽  
Best Fitting ◽  
Removal Of Arsenic

Abstract Arsenic contamination in the groundwater is a worldwide concern. Therefore, this study was designed to use synthetic iron-loaded goethite to remove arsenic. Adsorption was significantly pH-dependent; hence, pH values between 5.0 and 7.0 resulted in the highest removal of arsenate and arsenite. Langmuir and Freundlich isotherms were almost perfectly matched in terms of strong positive coefficient of determination “R2” arsenate – 0.941 and 0.992 and arsenite – 0.945 and 0.993. The adsorption intensity “n” resulted as arsenate – 2.542 and arsenite – 2.707; besides separation factor “RL” found as arsenate – 0.1 and arsenite – 0.5, respectively. However, both “n” and “RL” leads to a favourable adsorption process. Temkin isotherm yielded in equal binding energies “bt” showing as 0.004 (J/μg) for both arsenate and arsenite. Jovanovic monolayers isotherm was dominated by the Langmuir isotherm. This resulting in maximum adsorption capacity “Qmax” of arsenate – 1369.877 and arsenite – 1276.742 (μg/g), which approaches to the saturated binding sites. Kinetic data revealed that adsorption equilibrium was achieved in 240 – arsenate and 360 – arsenite (minutes), respectively. Chemisorption was found effective with high “R2” values 0.981 ­– arsenate and 0.994 – arsenite, respectively, with the best fitting of pseudo-second order. Moreover, Brunauer Emmett Teller (BET), Scanning Electron Microscopy (SEM), X-ray diffraction (XRD), and Fourier Transform Infrared Spectroscopy (FTIR) were used to determine the morphological content, surface area, crystalline structure, and chemical characteristics of the adsorbent. It is anticipated that optimal arsenic removal was achieved by the porosity, chemical bindings, and surface binding sites of the adsorbent.

scholarly journals Binding modes of potential anti-prion phytochemicals to PrPC structures in silico

2019 ◽  
Author(s):  
Sandesh Neupane ◽  
Jenisha Khadka ◽  
Sandesh Rayamajhi ◽  
Arti S. Pandey
Keyword(s):  
Steric Hindrance ◽  
Binding Sites ◽  
In Silico ◽  
Hydrophobic Interactions ◽  
Binding Energies ◽  
Surface Glycoprotein ◽  
Binding Modes ◽  
Cell Surface Glycoprotein ◽  
Chain Conformations

Abstract Background: Prion diseases involve the conversion of a normal, cell-surface glycoprotein (PrPC ) into a misfolded pathogenic form (PrPSC ). Cellular assays and in vivo experiments have identified various compounds with anti-prion activity which work through various mechanisms. Structures of PrPC have revealed the protein to occur in a swapped or non-swapped, monomeric or dimeric forms. Binding modes of known anti-prions is either not known, or has been determined with only the non-swapped structures of PrPC . In the current study medicinal phytochemicals from various databases have been docked with PrPC in silico to identify potential anti-prions in comparison with known anti-prion compounds to determine their binding modes and speculate possible mechanisms of inhibition of PrPC to PrPSC . Results: Eleven new phytochemicals were identified based on their binding energies and pharmacokinetic properties. The binding sites and interactions of the known and new anti-prion compounds are similar, and differences in binding modes occur in structures with very subtle differences in side chain conformations. Binding of these compounds poses steric hindrance to neighbouring molecules. Residues shown to be associated with inhibition of PrPC to PrPSC conversion form interactions with most of the compounds. Conclusions: The new compounds are mostly highly hydrophobic and are derivatives of terpenes, sterols and quinones. They might act as potent inhibitors of the PrPC to PrPSC conversion through a combination of steric hindrance and stabilization of structure through ionic/hydrophobic interactions. Their high binding energies coupled with identical binding sites as those of the known compounds, and their ability to cross the blood brain barrier makes these phytochemicals a promising group of compounds for further studies on prevention of PrPC to PrPSC .

Commentary: Pick's Disease Picks the Chicken. Or the Egg?

2020 ◽  
Vol 32 (4) ◽  
pp. 729
Author(s):  
Matthew L. Goodwin ◽  
Nahush A. Mokadam
Keyword(s):  
Pick's Disease ◽  
Pick’S Disease

Defective production and recognition of actions in Pick's disease with temporal lobe atrophy (semantic dementia)

2009 ◽  
Vol 29 (2) ◽  
pp. 268-276 ◽  
Author(s):  
Masaki Kondo ◽  
Satoshi Mochizuki ◽  
Mutsutaka Kobayakawa ◽  
Natsuko Tsuruya ◽  
Mitsuru Kawamura
Keyword(s):  
Temporal Lobe ◽  
Semantic Dementia ◽  
Pick's Disease ◽  
Pick’S Disease ◽  
Lobe Atrophy

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.

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