scholarly journals Structure-Based Discovery of Dual-Target Hits for Acetylcholinesterase and the α7 Nicotinic Acetylcholine Receptors: In Silico Studies and In Vitro Confirmation

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2872
Author(s):  
Sebastian Oddsson ◽  
Natalia M. Kowal ◽  
Philip K. Ahring ◽  
Elin S. Olafsdottir ◽  
Thomas Balle
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
In Silico ◽  
Ache Inhibitor ◽  
Complex Nature ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Α7 Nachr ◽  
In Silico Studies ◽  
Dual Target

Despite extensive efforts in the development of drugs for complex neurodegenerative diseases, treatment often remains challenging or ineffective, and hence new treatment strategies are necessary. One approach is the design of multi-target drugs, which can potentially address the complex nature of disorders such as Alzheimer’s disease. We report a method for high throughput virtual screening aimed at identifying new dual target hit molecules. One of the identified hits, N,N-dimethyl-1-(4-(3-methyl-[1,2,4]triazolo[4,3-a]pyrimidin-6-yl)phenyl)ethan-1-amine (Ýmir-2), has dual-activity as an acetylcholinesterase (AChE) inhibitor and as an α7 nicotinic acetylcholine receptor (α7 nAChR) agonist. Using computational chemistry methods, parallel and independent screening of a virtual compound library consisting of 3,848,234 drug-like and commercially available molecules from the ZINC15 database, resulted in an intersecting set of 57 compounds, that potentially possess activity at both of the two protein targets. Based on ligand efficiency as well as scaffold and molecular diversity, 16 of these compounds were purchased for in vitro validation by Ellman’s method and two-electrode voltage-clamp electrophysiology. Ýmir-2 was shown to exhibit the desired activity profile (AChE IC50 = 2.58 ± 0.96 µM; α7 nAChR activation = 7.0 ± 0.9% at 200 µM) making it the first reported compound with this particular profile and providing further evidence of the feasibility of in silico methods for the identification of novel multi-target hit molecules.

scholarly journals COVID-19 and Cholinergic Anti-inflammatory Pathway: In silico Identification of an Interaction between α7 Nicotinic Acetylcholine Receptor and the Cryptic Epitopes of SARS-CoV and SARS-CoV-2 Spike Glycoproteins

2020 ◽  
Author(s):  
George Lagoumintzis ◽  
Christos T. Chasapis ◽  
Nikolaos Alexandris ◽  
Socrates Tzartos ◽  
Elias Eliopoulos ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Molecular Model ◽  
Human Antibody ◽  
Protective Effects ◽  
Spike Glycoprotein ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Inflammatory Pathway ◽  
Α7 Nachr ◽  
Anti Inflammatory

ABSTRACTSARS-CoV-2 is the coronavirus that originated in Wuhan in December 2019 and has spread globally. The observation of a low prevalence of smokers among hospitalized COVID-19 patients has led to the development of a hypothesis that nicotine could have protective effects by enhancing the cholinergic anti-inflammatory pathway. Based on clinical data and on modelling and docking experiments we have previously presented the potential interaction between SARS-CoV-2 Spike glycoprotein and nicotinic acetylcholine receptors (nAChRs), due to a “toxin-like” epitope on the Spike Glycoprotein, with homology to a sequence of a snake venom toxin. We here present that this epitope coincides with the well-described cryptic epitope for the human antibody CR3022 and with the epitope for the recently described COVA1-16 antibody. Both antibodies are recognizing neighboring epitopes, are not interfering with the ACE2 protein and are not able to inhibit SARS-CoV and SARS-CoV-2 infections. In this study we present the molecular complexes of both SARS-CoV and SARS-CoV-2 Spike Glycoproteins, at their open or closed conformations, with the molecular model of the human α7 nAChR. We found that the interface of all studied protein complexes involves a large part of the “toxin-like” sequences of SARS-CoV and SARS-CoV-2 Spike glycoproteins and toxin binding site of human α7 nAChR.

scholarly journals Effects of C-Terminal Carboxylation on α-Conotoxin LsIA Interactions with Human α7 Nicotinic Acetylcholine Receptor: Molecular Simulation Studies

Marine Drugs ◽  
2019 ◽  
Vol 17 (4) ◽  
pp. 206 ◽  
Author(s):  
Jierong Wen ◽  
Andrew Hung
Keyword(s):  
Conformational Changes ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Salt Bridge ◽  
Md Simulations ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Α7 Nachr ◽  
C Terminus ◽  
Toxin Receptor

α-Conotoxins selectively bind to nicotinic acetylcholine receptors (nAChRs), which are therapeutic targets due to their important role in signaling transmission in excitable cells. A previous experimental study has demonstrated that carboxylation of the C-terminal of α-conotoxin LsIA reduces its potency to inhibit human α7 nAChR relative to naturally amidated LsIA. However, little is known about the contribution of conformational changes in the receptor and interactions, induced by C-terminal amidation/carboxylation of conotoxins, to selective binding to nAChRs, since most conotoxins and some disulfide-rich peptides from other conotoxin subfamilies possess a naturally amidated C-terminal. In this study, we employ homology modeling and molecular dynamics (MD) simulations to propose the determinants for differential interactions between amidated and carboxylated LsIAs with α7 nAChR. Our findings indicate an overall increased number of contacts favored by binding of amidated LsIA versus its carboxylated counterpart. Toxin-receptor pairwise interactions, which may play a role in enhancing the potency of the former, include ARG10-TRP77, LEU141 and CYS17-GLN79 via persistent hydrogen bonds and cation-π interactions, which are weakened in the carboxylated form due to a strong intramolecular salt-bridge formed by ARG10 and carboxylated C-terminus. The binding of amidated LsIA also induces enhanced movements in loop C and the juxtamembrane Cys-loop that are closely associated with receptor function. Additionally, the impacts of binding of LsIA on the overall structure and inter-subunit contacts were examined using inter-residue network analysis, suggesting a clockwise tilting of the α7 C and F loops upon binding to carboxylated LsIA, which is absent for amidated LsIA binding. The predicted molecular mechanism of LsIA binding to the α7 receptor may provide new insights into the important role of the C-terminal in the binding potency of conotoxins at neuronal nAChRs for pharmacological purposes.

In vitro and in silico studies on AChE inhibitory effects of a series of donepezil-like arylidene indanones

2020 ◽  
Vol 45 (4) ◽  
pp. 359-363
Author(s):  
Belgin Sever ◽  
Mehlika Dilek Altıntop ◽  
Halide Edip Temel
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Binding Mode ◽  
Docking Studies ◽  
Ache Inhibitor ◽  
Ache Inhibition ◽  
Lipinski’S Rule ◽  
In Silico Studies ◽  
Orally Bioavailable

AbstractObjectiveDonepezil is the most potent acetylcholinesterase (AChE) inhibitor currently available on the market for the management of Alzheimer’s disease. In this study, it was aimed to identify potent donepezil analogues.Materials and methodsThe effects of arylidene indanones (1–10) on AChE inhibition were examined using modified Ellman’s assay. Compound 4, the most potent arylidene indanone in this series, was subjected to molecular docking to anticipate its binding mode in the AChE site (PDB code: 4EY7). The pharmacokinetic profiles of all derivatives were also predicted.ResultsCompound 4 was found as the most potent AChE inhibitor with an IC50 value of 5.93 ± 0.29 μg/mL. According to molecular docking studies, compound 4 presented favorable interactions such as π–π interactions with Trp286 and Tyr337. In silico studies revealed that the compound did not violate Lipinski’s rule of five and Jorgensen’s rule of three, making it a potential orally bioavailable agent.ConclusionCompound 4 is a feasible candidate for further experiments related to AChE inhibition.

scholarly journals In silico studies of ASEM analogues targeting α7-nAChR and experimental verification

RSC Advances ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 3942-3951
Author(s):  
Yang Zhou ◽  
Guanglin Kuang ◽  
Junhao Li ◽  
Christer Halldin ◽  
Agneta Nordberg ◽  
...  
Keyword(s):  
Experimental Verification ◽  
In Silico ◽  
Free Energies ◽  
Binding Assays ◽  
Α7 Nachr ◽  
In Silico Studies ◽  
Binding Free Energies

The in silico binding free energies of the ASEM analogues targeting α7-nAChR are in line with the inhibition obtained from in vitro binding assays.

scholarly journals Blockade of Human α7 Nicotinic Acetylcholine Receptor by α-Conotoxin ImI Dendrimer: Insight from Computational Simulations

Marine Drugs ◽  
2019 ◽  
Vol 17 (5) ◽  
pp. 303 ◽  
Author(s):  
Xiaoxiao Xu ◽  
Jiazhen Liang ◽  
Zheyu Zhang ◽  
Tao Jiang ◽  
Rilei Yu
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Probes ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Gene Carriers ◽  
Α7 Nachr ◽  
Macromolecular Drugs ◽  
Stable Hydrogen Bond ◽  
Bond Network

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are involved in fast synaptic transmission and mediated physiological activities in the nervous system. α-Conotoxin ImI exhibits subtype-specific blockade towards homomeric α7 and α9 receptors. In this study, we established a method to build a 2×ImI-dendrimer/h (human) α7 nAChR model, and based on this model, we systematically investigated the molecular interactions between the 2×ImI-dendrimer and hα7 nAChR. Our results suggest that the 2×ImI-dendrimer possessed much stronger potency towards hα7 nAChR than the α-ImI monomer and demonstrated that the linker between α-ImI contributed to the potency of the 2×ImI-dendrimer by forming a stable hydrogen-bond network with hα7 nAChR. Overall, this study provides novel insights into the binding mechanism of α-ImI dendrimer to hα7 nAChR, and the methodology reported here opens an avenue for the design of more selective dendrimers with potential usage as drug/gene carriers, macromolecular drugs, and molecular probes.

Kamonolol acetate from Ferula pseudalliacea as AChE inhibitor: in vitro and in silico studies

2020 ◽  
Vol 31 (3) ◽  
pp. 965-973 ◽  
Author(s):  
Dara Dastan ◽  
Samane Validi ◽  
Ahmad Ebadi
Keyword(s):  
In Silico ◽  
Ache Inhibitor ◽  
In Silico Studies

scholarly journals In Silico Modeling of the α7 Nicotinic Acetylcholine Receptor: New Pharmacological Challenges Associated with Multiple Modes of Signaling

2020 ◽  
Vol 20 (10) ◽  
pp. 841-864 ◽  
Author(s):  
Alican Gulsevin ◽  
Roger L. Papke ◽  
Nicole Horenstein
Keyword(s):  
Ligand Binding ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
In Silico ◽  
Receptor Activation ◽  
Binding Studies ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
High Calcium ◽  
In Silico Studies

The α7 nicotinic acetylcholine receptor is a homopentameric ion-channel of the Cys-loop superfamily characterized by its low probability of opening, high calcium permeability, and rapid desensitization. The α7 receptor has been targeted for the treatment of the cognitive symptoms of schizophrenia, depression, and Alzheimer’s disease, but it is also involved in inflammatory modulation as a part of the cholinergic anti-inflammatory pathway. Despite its functional importance, in silico studies of the α7 receptor cannot produce a general model explaining the structural features of receptor activation, nor predict the mode of action for various ligand classes. Two particular problems in modeling the α7 nAChR are the absence of a high-resolution structure and the presence of five potentially nonequivalent orthosteric ligand binding sites. There is wide variability regarding the templates used for homology modeling, types of ligands investigated, simulation methods, and simulation times. However, a systematic survey focusing on the methodological similarities and differences in modeling α7 has not been done. In this work, we make a critical analysis of the modeling literature of α7 nAChR by comparing the findings of computational studies with each other and with experimental studies under the main topics of structural studies, ligand binding studies, and comparisons with other nAChR. In light of our findings, we also summarize current problems in the field and make suggestions for future studies concerning modeling of the α7 receptor.

scholarly journals In Vitro and In Vivo Characterization of Dibenzothiophene Derivatives [125I]Iodo-ASEM and [18F]ASEM as Radiotracers of Homo- and Heteromeric α7 Nicotinic Acetylcholine Receptors

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1425 ◽  
Author(s):  
Cornelius K. Donat ◽  
Henrik H. Hansen ◽  
Hanne D. Hansen ◽  
Ronnie C. Mease ◽  
Andrew G. Horti ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Published Data ◽  
Kinetic Properties ◽  
Binding Properties ◽  
Nicotinic Acetylcholine ◽  
Pig Brain ◽  
Α7 Nachr ◽  
Deficient Mice

The α7 nicotinic acetylcholine receptor (α7 nAChR) is involved in several cognitive and physiologic processes; its expression levels and patterns change in neurologic and psychiatric diseases, such as schizophrenia and Alzheimer’s disease, which makes it a relevant drug target. Development of selective radioligands is important for defining binding properties and occupancy of novel molecules targeting the receptor. We tested the in vitro binding properties of [125I]Iodo-ASEM [(3-(1,4-diazabycyclo[3.2.2]nonan-4-yl)-6-(125I-iododibenzo[b,d]thiopentene 5,5-dioxide)] in the mouse, rat and pig brain using autoradiography. The in vivo binding properties of [18F]ASEM were investigated using positron emission tomography (PET) in the pig brain. [125I]Iodo-ASEM showed specific and displaceable high affinity (~1 nM) binding in mouse, rat, and pig brain. Binding pattern overlapped with [125I]α-bungarotoxin, specific binding was absent in α7 nAChR gene-deficient mice and binding was blocked by a range of α7 nAChR orthosteric modulators in an affinity-dependent order in the pig brain. Interestingly, relative to the wild-type, binding in β2 nAChR gene-deficient mice was lower for [125I]Iodo-ASEM (58% ± 2.7%) than [125I]α-bungarotoxin (23% ± 0.2%), potentially indicating different binding properties to heteromeric α7β2 nAChR. [18F]ASEM PET in the pig showed high brain uptake and reversible tracer kinetics with a similar spatial distribution as previously reported for α7 nAChR. Blocking with SSR-180,711 resulted in a significant decrease in [18F]ASEM binding. Our findings indicate that [125I]Iodo-ASEM allows sensitive and selective imaging of α7 nAChR in vitro, with better signal-to-noise ratio than previous tracers. Preliminary data of [18F]ASEM in the pig brain demonstrated principal suitable kinetic properties for in vivo quantification of α7 nAChR, comparable to previously published data.

Recent In Vitro and In Silico Advances in the Understanding of Intranasal Drug Delivery

2020 ◽  
Vol 26 ◽  
Author(s):  
John Chen ◽  
Andrew Martin ◽  
Warren H. Finlay
Keyword(s):  
Drug Delivery ◽  
In Silico ◽  
Local Drug Delivery ◽  
In Vivo Studies ◽  
Intranasal Drug Delivery ◽  
Nasal Sprays ◽  
In Silico Studies ◽  
Drug Delivery Devices

Background: Many drugs are delivered intranasally for local or systemic effect, typically in the form of droplets or aerosols. Because of the high cost of in vivo studies, drug developers and researchers often turn to in vitro or in silico testing when first evaluating the behavior and properties of intranasal drug delivery devices and formulations. Recent advances in manufacturing and computer technologies have allowed for increasingly realistic and sophisticated in vitro and in silico reconstructions of the human nasal airways. Objective: To perform a summary of advances in understanding of intranasal drug delivery based on recent in vitro and in silico studies. Conclusion: The turbinates are a common target for local drug delivery applications, and while nasal sprays are able to reach this region, there is currently no broad consensus across the in vitro and in silico literature concerning optimal parameters for device design, formulation properties and patient technique which would maximize turbinate deposition. Nebulizers are able to more easily target the turbinates, but come with the disadvantage of significant lung deposition. Targeting of the olfactory region of the nasal cavity has been explored for potential treatment of central nervous system conditions. Conventional intranasal devices, such as nasal sprays and nebulizers, deliver very little dose to the olfactory region. Recent progress in our understanding of intranasal delivery will be useful in the development of the next generation of intranasal drug delivery devices.

In-silico Studies of Isolated Phytoalkaloid Against Lipoxygenase: Study Based on Possible Correlation

2018 ◽  
Vol 21 (3) ◽  
pp. 215-221
Author(s):  
Haroon Khan ◽  
Muhammad Zafar ◽  
Helena Den-Haan ◽  
Horacio Perez-Sanchez ◽  
Mohammad Amjad Kamal
Keyword(s):  
In Silico ◽  
Docking Studies ◽  
In Vivo Studies ◽  
In Vitro Assays ◽  
Chronic Obstructive ◽  
Lipoxygenase Inhibitors ◽  
Lipoxygenase Inhibition ◽  
In Silico Studies

Aim and Objective: Lipoxygenase (LOX) enzymes play an important role in the pathophysiology of several inflammatory and allergic diseases including bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis and chronic obstructive pulmonary disease. Inhibitors of the LOX are believed to be an ideal approach in the treatment of diseases caused by its over-expression. In this regard, several synthetic and natural agents are under investigation worldwide. Alkaloids are the most thoroughly investigated class of natural compounds with outstanding past in clinically useful drugs. In this article, we have discussed various alkaloids of plant origin that have already shown lipoxygenase inhibition in-vitro with possible correlation in in silico studies. Materials and Methods: Molecular docking studies were performed using MOE (Molecular Operating Environment) software. Among the ten reported LOX alkaloids inhibitors, derived from plant, compounds 4, 2, 3 and 1 showed excellent docking scores and receptor sensitivity. Result and Conclusion: These compounds already exhibited in vitro lipoxygenase inhibition and the MOE results strongly correlated with the experimental results. On the basis of these in vitro assays and computer aided results, we suggest that these compounds need further detail in vivo studies and clinical trial for the discovery of new more effective and safe lipoxygenase inhibitors. In conclusion, these results might be useful in the design of new and potential lipoxygenase (LOX) inhibitors.

Sign in / Sign up

Export Citation Format

Share Document