scholarly journals Cannabis Constituents and Acetylcholinesterase Interaction: Molecular Docking, In Vitro Studies and Association with CNR1 rs806368 and ACHE rs17228602

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 758
Author(s):  
Tiyyaba Furqan ◽  
Sidra Batool ◽  
Rabia Habib ◽  
Mamoona Shah ◽  
Huba Kalasz ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cannabinoid Receptor ◽  
Human Subjects ◽  
Inhibitory Effect ◽  
Ache Inhibitor ◽  
Binding Affinities ◽  
Cannabinoid Receptor 1 ◽  
Inhibitory Potential

The study documented here was aimed to find the molecular interactions of some of the cannabinoid constituents of cannabis with acetylcholinesterase (AChE). Molecular docking and LogP determination were performed to predict the AChE inhibitory effect and lipophilicity. AChE enzyme activity was measured in the blood of cannabis addicted human subjects. Further, genetic predisposition to cannabis addiction was investigated by association analysis of cannabinoid receptor 1 (CNR1) single nucleotide polymorphism (SNP) rs806368 and ACHE rs17228602 using restriction fragment length polymorphism (RFLP) method. All the understudied cannabis constituents showed promising binding affinities with AChE and are lipophilic in nature. The AChE activity was observed to be indifferent in cannabis addicted and non-addicted healthy controls. There was no significant association with CNR1 SNP rs806368 and ACHE rs17228602. The study concludes that in silico prediction for individual biomolecules of cannabis is different from in vivo physiological action in human subjects when all are present together. However, for a deeper mechanistic insight into these interactions and association, multi-population studies are suggested. Further studies to explore the inhibitory potential of different cannabis constituents for intended AChE inhibitor-based drug are warranted.

scholarly journals An Analysis Based on Molecular Docking and Molecular Dynamics Simulation Study of Bromelain as Anti-SARS-CoV-2 Variants

2021 ◽  
Vol 12 ◽  
Author(s):  
Trina Ekawati Tallei ◽  
Fatimawali ◽  
Afriza Yelnetty ◽  
Rinaldi Idroes ◽  
Diah Kusumawaty ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Three Dimensional ◽  
Md Simulations ◽  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Novel Coronavirus

The rapid spread of a novel coronavirus known as SARS-CoV-2 has compelled the entire world to seek ways to weaken this virus, prevent its spread and also eliminate it. However, no drug has been approved to treat COVID-19. Furthermore, the receptor-binding domain (RBD) on this viral spike protein, as well as several other important parts of this virus, have recently undergone mutations, resulting in new virus variants. While no treatment is currently available, a naturally derived molecule with known antiviral properties could be used as a potential treatment. Bromelain is an enzyme found in the fruit and stem of pineapples. This substance has been shown to have a broad antiviral activity. In this article, we analyse the ability of bromelain to counteract various variants of the SARS-CoV-2 by targeting bromelain binding on the side of this viral interaction with human angiotensin-converting enzyme 2 (hACE2) using molecular docking and molecular dynamics simulation approaches. We have succeeded in making three-dimensional configurations of various RBD variants using protein modelling. Bromelain exhibited good binding affinity toward various variants of RBDs and binds right at the binding site between RBDs and hACE2. This result is also presented in the modelling between Bromelain, RBD, and hACE2. The molecular dynamics (MD) simulations study revealed significant stability of the bromelain and RBD proteins separately up to 100 ns with an RMSD value of 2 Å. Furthermore, despite increases in RMSD and changes in Rog values of complexes, which are likely due to some destabilized interactions between bromelain and RBD proteins, two proteins in each complex remained bonded, and the site where the two proteins bind remained unchanged. This finding indicated that bromelain could have an inhibitory effect on different SARS-CoV-2 variants, paving the way for a new SARS-CoV-2 inhibitor drug. However, more in vitro and in vivo research on this potential mechanism of action is required.

scholarly journals Evaluation of cannabidiol’s inhibitory effect on alpha-glucosidase and its stability in simulated gastric and intestinal fluids

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Hang Ma ◽  
Huifang Li ◽  
Chang Liu ◽  
Navindra P. Seeram
Keyword(s):  
Molecular Docking ◽  
High Performance ◽  
Inhibitory Effect ◽  
In Vitro Assays ◽  
Inhibitory Effects ◽  
In Vivo Models ◽  
Glucosidase Activity ◽  
Intestinal Fluids

Abstract Objective Cannabidiol (CBD) has been reported to have anti-diabetic effects in pre-clinical and clinical studies but its inhibitory effects on α-glucosidase, a carbohydrate hydrolyzing enzyme, remain unknown. Herein, we evaluated CBD’s inhibitory effects on α-glucosidase using in vitro assays and computational studies. Methods CBD’s inhibitory effect on α-glucosidase activity was evaluated in a yeast enzymatic assay and by molecular docking. The stability of CBD in simulated gastric and intestinal fluids was evaluated by high-performance liquid chromatography analyses. Results CBD, at 10, 19, 38, 76, 152, 304, 608, and 1216 μM, inhibited α-glucosidase activity with inhibition of 17.1, 20.4, 48.1, 56.6, 59.1, 63.7, 74.1, and 95.4%, respectively. Acarbose, the positive control, showed a comparable inhibitory activity (with 85.1% inhibition at 608 μM). CBD’s inhibitory effect on α-glucosidase was supported by molecular docking showing binding energy (-6.39 kcal/mol) and interactions between CBD and the α-glucosidase protein. CBD was stable in simulated gastric and intestinal fluids for two hours (maintained ≥ 90.0%). Conclusions CBD showed moderate inhibitory effect against yeast α-glucosidase activity and was stable in gastric and intestinal fluids. However, further studies on CBD’s anti-α-glucosidase effects using cellular and in vivo models are warranted to support its potential application for the management of type II diabetes mellitus.

scholarly journals Theoretical Exploring of a Molecular Mechanism for Melanin Inhibitory Activity of Calycosin in Zebrafish

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6998
Author(s):  
Nilupaier Tayier ◽  
Ning-Yi Qin ◽  
Li-Nan Zhao ◽  
Yi Zeng ◽  
Yu Wang ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Energy Analysis ◽  
Kojic Acid ◽  
Inhibitory Effect ◽  
In Vivo Model ◽  
In Vitro Test ◽  
Free Energy Analysis

Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin in the human body. Overproduction of melanin can lead to a variety of skin disorders. Calycosin is an isoflavone from Astragali Radix, which is a traditional Chinese medicine that exhibits several pharmacological activities including skin whitening. In our study, the inhibitory effect of calycosin on melanin production is confirmed in a zebrafish in vivo model by comparing with hydroquinone, kojic acid, and arbutin, known as tyrosinase inhibitors. Moreover, the inhibitory kinetics of calycosin on tyrosinase and their binding mechanisms are determined using molecular docking techniques, molecular dynamic simulations, and free energy analysis. The results indicate that calycosin has an obvious inhibitory effect on zebrafish pigmentation at the concentration of 7.5 μM, 15 μM, and 30 μM. The IC50 of calycosin is 30.35 μM, which is lower than hydroquinone (37.35 μM), kojic acid (6.51 × 103 μM), and arbutin (3.67 × 104 μM). Furthermore, all the results of molecular docking, molecular dynamics simulations, and free energy analysis suggest that calycosin can directly bind to the active site of tyrosinase with very good binding affinity. The study indicates that the combination of computer molecular modeling and zebrafish in vivo assay would be feasible in confirming the result of the in vitro test and illustrating the target-binding information.

Cannabinoid receptor 1 and acute resistance exercise – In vivo and in vitro studies in human skeletal muscle

Peptides ◽  
2015 ◽  
Vol 67 ◽  
pp. 55-63 ◽  
Author(s):  
Satu Pekkala ◽  
Petri Wiklund ◽  
Juha J. Hulmi ◽  
Eija Pöllänen ◽  
Varpu Marjomäki ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Resistance Exercise ◽  
Human Skeletal Muscle ◽  
Cannabinoid Receptor ◽  
In Vitro Studies ◽  
Cannabinoid Receptor 1

Potential neurotoxicity of a novel aminoacridine analogue

1995 ◽  
Vol 14 (6) ◽  
pp. 469-474 ◽  
Author(s):  
TM Walker ◽  
B. Starr ◽  
BB Dewhurst ◽  
C. Atterwill
Keyword(s):  
Neuroblastoma Cell ◽  
Neutral Red ◽  
Neuroblastoma Cell Line ◽  
In Vivo Studies ◽  
Ache Inhibitor ◽  
The Novel ◽  
Tertiary Butyl ◽  
Inhibitory Potential

1 A class of compounds, 9-aminoacridines, have long been known to be reversible inhibitors of acetyl cholinesterase (AChE - EC 3.1.1.7), the most familiar of which is 9-amino-1,2,3,4-tetrahydroacridine (Tacrine). 2 A novel aminoacridine was synthesised: - 2-tertiary butyl-9-amino-1,2,3,4-tetrahydroacridine (2tBuTHA). 3 In vitro comparisons of the acetylcholinesterase inhibitory potential and neurotoxicity compared to Tacrine were performed using a chemically differentiated neuroblastoma cell line (Neuro 2A). 2tBuTHA, but not Tacrine, was cytotoxic to the neural cell following 20 h exposure, despite being the least potent AChE inhibitor (IC80 AChE 12.53 μM +/- 1.14 s.e.m., Neutral Red Uptake IC50 9.53 μM +/- 0.98 s.e.m., MTT Reduction IC80 14.6 μM +/- 1.43 s.e.m.). 4 In vivo studies used a novel application of a five arm radial maze to assess neuropharmacological effects on working memory in control and Scopolamine (1 mg kg-1 i.p.) treated mice. There was an impairment of short term cognitive function with 2tBuTHA (15 mg kg -1 i.p.), but not Tacrine (10 mg kg-1 i.p.) which improved the Scopolamine deficit as expected. 5 This combined in vitro and in vivo data infers a neuro toxic property for the novel compound 2tBuTHA, a close structural analogue of Tacrine.

scholarly journals Lack of Correlation between In Vitro and In Vivo Studies on the Inhibitory Effects of (‒)-Sophoranone on CYP2C9 Is Attributable to Low Oral Absorption and Extensive Plasma Protein Binding of (‒)-Sophoranone

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 328
Author(s):  
Yu Fen Zheng ◽  
Soo Hyeon Bae ◽  
Zhouchi Huang ◽  
Soon Uk Chae ◽  
Seong Jun Jo ◽  
...  
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Oral Absorption ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Inhibitory Potential

(‒)-Sophoranone (SPN) is a bioactive component of Sophora tonkinensis with various pharmacological activities. This study aims to evaluate its in vitro and in vivo inhibitory potential against the nine major CYP enzymes. Of the nine tested CYPs, it exerted the strongest inhibitory effect on CYP2C9-mediated tolbutamide 4-hydroxylation with the lowest IC50 (Ki) value of 0.966 ± 0.149 μM (0.503 ± 0.0383 μM), in a competitive manner. Additionally, it strongly inhibited other CYP2C9-catalyzed diclofenac 4′-hydroxylation and losartan oxidation activities. Upon 30 min pre-incubation of human liver microsomes with SPN in the presence of NADPH, no obvious shift in IC50 was observed, suggesting that SPN is not a time-dependent inactivator of the nine CYPs. However, oral co-administration of SPN had no significant effect on the pharmacokinetics of diclofenac and 4′-hydroxydiclofenac in rats. Overall, SPN is a potent inhibitor of CYP2C9 in vitro but not in vivo. The very low permeability of SPN in Caco-2 cells (Papp value of 0.115 × 10−6 cm/s), which suggests poor absorption in vivo, and its high degree of plasma protein binding (>99.9%) may lead to the lack of in vitro–in vivo correlation. These findings will be helpful for the safe and effective clinical use of SPN.

scholarly journals Inhibitory Effect of PlantManilkara subsericeaagainst Biological Activities ofLachesis mutaSnake Venom

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Eduardo Coriolano De Oliveira ◽  
Caio Pinho Fernandes ◽  
Eladio Flores Sanchez ◽  
Leandro Rocha ◽  
André Lopes Fuly
Keyword(s):  
Ethyl Acetate ◽  
Snake Venom ◽  
Biological Activities ◽  
Inhibitory Effect ◽  
Snake Venoms ◽  
Brazilian Flora ◽  
Inhibitory Potential ◽  
Lachesis Muta

Snake venom is composed of a mixture of substances that caused in victims a variety of pathophysiological effects. Besides antivenom, literature has described plants able to inhibit injuries and lethal activities induced by snake venoms. This work describes the inhibitory potential of ethanol, hexane, ethyl acetate, or dichloromethane extracts and fractions from stem and leaves ofManilkara subsericeaagainstin vivo(hemorrhagic and edema) andin vitro(clotting, hemolysis, and proteolysis) activities caused byLachesis mutavenom. All the tested activities were totally or at least partially reduced byM. subsericea. However, whenL. mutavenom was injected into mice 15 min first or after the materials, hemorrhage and edema were not inhibited. Thus,M. subsericeacould be used as antivenom in snakebites ofL. muta. And, this work also highlights Brazilian flora as a rich source of molecules with antivenom properties.

scholarly journals qNMR quantification and in silico analysis of isobrucein B and neosergeolide from Picrolemma sprucei as potential inhibitors of SARS-CoV-2 protease (3CLpro) and RNA-dependent RNA polymerase (RdRp) and pharmacokinetic and toxicological properties

2021 ◽  
Vol 10 (16) ◽  
pp. e69101623220
Author(s):  
Marcos Túlio da Silva ◽  
Matheus Gabriel de Oliveira ◽  
José Realino de Paula ◽  
Vinicius Barreto da Silva ◽  
Kidney de Oliveira Gomes Neves ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Medicinal Plant ◽  
In Silico ◽  
Active Sites ◽  
In Silico Analysis ◽  
In Vivo Experiments ◽  
Inhibitory Potential ◽  
Potential Inhibitors

Objective: To quantify the quassinoids of P. sprucei, a medicinal plant that is native to the Amazon region, using qNMR and investigate the inhibitory potential of isobrucein B and neosergeolide on the 3CLpro and RdRp targets of SARS-CoV-2 through in silico approaches. Methods: the quantification was performed in a fraction (F2-F3) enriched with the quassinoids isobrucein B and neosergeolide using the PULCON method. In silico assays were performed using molecular docking to assess interactions and binding affinity between neosergeolide and isobrucein B ligands with SARS-CoV-2 3CLpro and RdRp targets, and online servers were used to estimate pharmacokinetic and toxicity. Results: It was possible to determine the quantity of the two quassinoids isobrucein B and neosergeolide in the F2-F3 fraction (769.6 mg), which were present in significant amounts in the PsMeOH extract (5.46%). The results of the docking analysis, based on the crystallized structures of RdRp and 3CLpro, indicated that isobrucein B and neosergeolide are potential inhibitors of the two proteins evaluated, as well as showing the importance of hydrogen bonding and pi (π) interactions for the active sites foreseen for each target. Conclusion: The results suggest that P. sprucei quassinoids may interact with 3CLpro and RdRp targets. In vitro and in vivo experiments are needed to confirm the results of molecular docking and investigate the risks of using P. sprucei as a medicinal plant against COVID-19.

The Effect of Barbituric Acid Derivatives on Platelet Function in Vitro and in Vivo

1973 ◽  
Vol 30 (02) ◽  
pp. 315-326
Author(s):  
J. Heinz Joist ◽  
Jean-Pierre Cazenave ◽  
J. Fraser Mustard
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Barbituric Acid ◽  
Platelet Rich Plasma ◽  
Inhibitory Effect ◽  
Primary Response ◽  
Sodium Pentobarbital ◽  
Barbituric Acid Derivatives

SummarySodium pentobarbital (SPB) and three other barbituric acid derivatives were found to inhibit platelet function in vitro. SPB had no effect on the primary response to ADP of platelets in platelet-rich plasma (PRP) or washed platelets but inhibited secondary aggregation induced by ADP in human PRP. The drug inhibited both phases of aggregation induced by epinephrine. SPB suppressed aggregation and the release reaction induced by collagen or low concentrations of thrombin, and platelet adherence to collagen-coated glass tubes. The inhibition by SPB of platelet aggregation was readily reversible and isotopically labeled SPB did not become firmly bound to platelets. No inhibitory effect on platelet aggregation induced by ADP, collagen, or thrombin could be detected in PRP obtained from rabbits after induction of SPB-anesthesia.

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