scholarly journals Study of Baicalin toward COVID-19 Treatment: In silico Target Analysis and in vitro Inhibitory Effects on SARS-CoV-2 Proteases

2021 ◽  
pp. 122-137
Author(s):  
Chingju Lin ◽  
Fuu-Jen Tsai ◽  
Yuan-Man Hsu ◽  
Tsung-Jung Ho ◽  
Guo-Kai Wang ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Pathway Analysis ◽  
Acute Inflammation ◽  
Inhibitory Effect ◽  
Pharmacological Effects ◽  
Inhibitory Effects ◽  
Rna Dependent Rna Polymerase ◽  
Negative Impacts

Negative impacts of COVID-19 on human health and economic and social activities urge scientists to develop effective treatments. Baicalin is a natural flavonoid, extracted from a traditional medicinal plant, previously reported with anti-inflammatory activity. In this study, we used pharmacophore fitting and molecular docking to screen and determine docking patterns and the binding affinity of baicalin on 3 major targets of SARS-CoV-2 (3-chymotrypsin-like cysteine protease [3CLpro], papain-like protease [PLpro], and RNA-dependent RNA polymerase). The obtained data revealed that baicalin has high pharmacophore fitting on 3CLpro and predicted good binding affinity on PLpro. Moreover, using the enzymatic assay, we examined the inhibitory effect of baicalin in vitro on the screened enzymes. Baicalin also exhibits inhibitory effect on these proteases in vitro. Additionally, we performed pharmacophore-based screening of baicalin on human targets and conducted pathway analysis to explore the potential cytoprotective effects of baicalin in the host cell that may be beneficial for COVID-19 treatment. The result suggested that baicalin has multiple targets in human cell that may induce multiple pharmacological effects. The result of pathway analysis implied that these targets may be associated with baicalin-induced bioactivities that are involved with signals of pro-inflammation factors, such as cytokine and chemokine. Taken together with supportive data from the literature, the bioactivities of bailalin may be beneficial for COVID-19 treatment by reducing cytokine-induced acute inflammation. In conclusion, baicalin is potentially a good candidate for developing new therapeutic to treat COVID-19.

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.

In Vitro Effects of Ethanol on Rabbit Platelet Aggregation, Secretion of Granule Contents, and Cyclic AMP Levels in the Presence of Prostacyclin

1989 ◽  
Vol 61 (02) ◽  
pp. 254-258 ◽  
Author(s):  
Margaret L Rand ◽  
Peter L Gross ◽  
Donna M Jakowec ◽  
Marian A Packham ◽  
J Fraser Mustard
Keyword(s):  
Cyclic Amp ◽  
Inhibitory Effect ◽  
Rabbit Platelet ◽  
Inhibitory Effects ◽  
Low Concentrations ◽  
Rabbit Platelets ◽  
High Concentrations ◽  
In Vitro Effects ◽  
Aggregation Of Platelets

SummaryEthanol, at physiologically tolerable concentrations, inhibits platelet responses to low concentrations of collagen or thrombin, but does not inhibit responses of washed rabbit platelets stimulated with high concentrations of ADP, collagen, or thrombin. However, when platelet responses to high concentrations of collagen or thrombin had been partially inhibited by prostacyclin (PGI2), ethanol had additional inhibitory effects on aggregation and secretion. These effects were also observed with aspirin- treated platelets stimulated with thrombin. Ethanol had no further inhibitory effect on aggregation of platelets stimulated with ADP, or the combination of ADP and epinephrine. Thus, the inhibitory effects of ethanol on platelet responses in the presence of PGI2 were very similar to its inhibitory effects in the absence of PGI2, when platelets were stimulated with lower concentrations of collagen or thrombin. Ethanol did not appear to exert its inhibitory effects by increasing cyclic AMP above basal levels and the additional inhibitory effects of ethanol in the presence of PGI2 did not appear to be brought about by further increases in platelet cyclic AMP levels.

scholarly journals Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Vicky Mody ◽  
Joanna Ho ◽  
Savannah Wills ◽  
Ahmed Mawri ◽  
Latasha Lawson ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Inhibitory Effects ◽  
Major Threat ◽  
Main Protease ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Computational Molecular Modeling

AbstractEmerging outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is a major threat to public health. The morbidity is increasing due to lack of SARS-CoV-2 specific drugs. Herein, we have identified potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.

scholarly journals Amphetamine-Decreased Progesterone and Estradiol Release in Rat Granulosa Cells: The Regulatory Role of cAMP- and Ca2+-Mediated Signaling Pathways

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 493
Author(s):  
 Chung-Yu Chen ◽  
Chien-Rung Chen ◽  
Chiao-Nan Chen ◽  
Paulus S. Wang ◽  
Toby Mündel ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Prostaglandin F2α ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Steroidogenic Enzyme ◽  
Estradiol Secretion ◽  
Basal Release ◽  
Ca2 Channels

The purpose of this study is to evaluate the amphetamine effects on progesterone and estradiol production in rat granulosa cells and the underlying cellular regulatory mechanisms. Freshly dispersed rat granulosa cells were cultured with various test drugs in the presence of amphetamine, and the estradiol/progesterone production and the cytosolic cAMP level were measured. Additionally, the cytosolic-free Ca2+ concentrations ([Ca2+]i) were measured to examine the role of Ca2+ influx in the presence of amphetamine. Amphetamine in vitro inhibited both basal and porcine follicle-stimulating hormone-stimulated estradiol/progesterone release, and amphetamine significantly decreased steroidogenic enzyme activities. Adding 8-Bromo-cAMP did not recover the inhibitory effects of amphetamine on progesterone and estradiol release. H89 significantly decreased progesterone and estradiol basal release but failed to enhance a further amphetamine inhibitory effect. Amphetamine was capable of further suppressing the release of estradiol release under the presence of nifedipine. Pretreatment with the amphetamine for 2 h decreased the basal [Ca2+]i and prostaglandin F2α-stimulated increase of [Ca2+]i. Amphetamine inhibits progesterone and estradiol secretion in rat granulosa cells through a mechanism involving decreased PKA-downstream steroidogenic enzyme activity and L-type Ca2+ channels. Our current findings show that it is necessary to study the possibility of amphetamine perturbing reproduction in females.

scholarly journals In Vitro α-Glucosidase and α-Amylase Inhibitory Activities of Free and Bound Phenolic Extracts from the Bran and Kernel Fractions of Five Sorghum Grain Genotypes

Foods ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1301
Author(s):  
Yun Xiong ◽  
Ken Ng ◽  
Pangzhen Zhang ◽  
Robyn Dorothy Warner ◽  
Shuibao Shen ◽  
...  
Keyword(s):  
Digestive System ◽  
Inhibitory Concentration ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Phenolic Contents ◽  
Inhibitory Activities ◽  
Sorghum Grain ◽  
Global Health Challenge ◽  
Phenolic Extracts

Diabetes is a global health challenge. Currently, an effective treatment for diabetes is to reduce the postprandial hyperglycaemia by inhibiting the carbohydrate hydrolysing enzymes in the digestive system. In this study, we investigated the in vitro α-glucosidase and α-amylase inhibitory effects of free and bound phenolic extracts, from the bran and kernel fractions of five sorghum grain genotypes. The results showed that the inhibitory effect of sorghum phenolic extracts depended on the phenolic concentration and composition. Sorghum with higher phenolic contents generally had higher inhibitory activity. Among the tested extracts, the brown sorghum (IS131C)-bran-free extract (BR-bran-free, half-maximal inhibitory concentration (IC50) = 18 ± 11 mg sorghum/mL) showed the strongest inhibition against α-glucosidase which was comparable to that of acarbose (IC50 = 1.39 ± 0.23 mg acarbose/mL). The red sorghum (Mr-Buster)-kernel-bound extract (RM-kernel-bound, IC50 = 160 ± 12 mg sorghum/mL) was the most potent in inhibiting α-amylase but was much weaker compared to acarbose (IC50 = 0.50 ± 0.03 mg acarbose/mL).

A STUDY OF THE INHIBITORY EFFECTS OF CHICK WHOLE EYE EXTRACT ON THE DEVELOPMENT OF THE LENS OF THE CHICK EMBRYO IN VITRO

1966 ◽  
Vol 44 (4) ◽  
pp. 661-676 ◽  
Author(s):  
Robert P. Thompson
Keyword(s):  
Chick Embryo ◽  
Nutrient Medium ◽  
Inhibitory Effect ◽  
Reactive System ◽  
Vesicle Formation ◽  
Inhibitory Effects ◽  
Muscle Extract ◽  
Lens Vesicle ◽  
And Control

To demonstrate the phenomenon of homologous inhibition by clearly interpretable results in a readily reactive system, experiments were carried out to study the effect of chick whole eye extract on the development of the vesicular lens of the chick embryo in vitro. The heads of embryos of 11 through 13 somites were explanted onto nutrient medium diluted with varying amounts of the extract, and cultured for 30 hours. A total of 35 embryos exposed to concentrations of 1:1, 1:2, and 1:4 (extract to medium) showed complete inhibition of lens vesicle formation. Of a total of 53 embryos on concentrations of 1:8, 1:16, 1:32, and 1:64, more than 50% showed inhibition of vesicle formation. The inhibitory effect disappeared at a concentration of 1:128. Control material exposed to some equivalent concentrations of nutrient medium – saline mixtures showed inhibition of vesicle formation in only 15% of 33 embryos. Of a total of 27 control embryos exposed to ventricular muscle extract, approximately one-third showed inhibition of vesicle formation at concentrations of 1:8 and 1:16, with the inhibitory effect disappearing at 1:32. The implications of this result are discussed. Other factors and control experiments are described and their value is assessed.

Potent Anticancer Activities of Beauvericin against KB cells In Vitro by Inhibiting the Expression of ACAT1 and Exploring Binding Affinity

2021 ◽  
Vol 21 ◽  
Author(s):  
Haiming Zhou ◽  
Jing Zhang ◽  
Xiaoqing Chen ◽  
Shili Guo ◽  
Huimei Lin ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cell Line ◽  
Binding Affinity ◽  
X Ray Diffraction ◽  
Kb Cells ◽  
Anticancer Activities ◽  
Monoclinic Crystal ◽  
X Ray ◽  
Multiple Tumor

Background and Objective: Beauvericin (BEA), a cyclic hexadepsipeptide mycotoxin, is a potent inhibitor of the acyl-CoA: cholesterol acyltransferase enzyme 1 (ACAT1) which involved in multiple tumor-correlated pathways. However, the binding mechanisms between BEA and ACAT1 were not elucidated. Methods: BEA was purified from a mangrove entophytic Fusarium sp. KL11. Single-crystal X-ray diffraction was used to determine the structure of BEA. Wound healing assays of BEA against KB cell line and MDA-MB-231 cell line were evaluated. Inhibitory potency of BEA against ACAT1 was determined by ELISA assays. Molecular docking was carried out to illuminate the bonding mechanism between BEA and ACAT1. Results: The structure of BEA was confirmed by X-ray diffraction, indicating a monoclinic crystal system with P21 space group (α = 90°, β = 92.2216(9)o, γ= 90o). BEA displayed migration-inhibitory activities against KB cells and MDA-MB-231 cells in vitro. ELISA assays revealed the protein expression level of ACAT1 in KB cells was significantly decreased after BEA treatment (P ＜0.05). Molecular docking demonstrated that BEA formed hydrogen bond with His425 and pi-pi staking with Tyr429 in ACAT1. Conclusions: BEA sufficiently inhibited the proliferation and migration of KB cells and MDA-MB-231 cells by downregulating ACAT1 expression. In addition, BEA potentially possessed a strong binding affinity with ACAT1. BEA may serve as a potential lead compound for the development of a new ACAT1-targeted anticancer drug.

scholarly journals SUSTAINED RELEASE TABLETS OF SORAFENIB-SILIBININ COMBINATIONS FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA

2018 ◽  
Vol 10 (5) ◽  
pp. 117
Author(s):  
Savita Mishra ◽  
Sandhya Hora ◽  
Vibha Shukla ◽  
Mukul Das ◽  
Harsha Kharkwal ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Drug Release ◽  
Sustained Release ◽  
Cell Line ◽  
Binding Affinity ◽  
Drug Combination ◽  
Docking Studies ◽  
Molecular Docking Studies ◽  
Weight Variation

Objective: The aim of this study was to develop polymer coated sustained release tablet using sorafenib and silibinin combination for the treatment of hepatocellular carcinoma.Methods: The qualitative analysis such as weight variation, friability, hardness, interaction studies, disintegration and in vitro release were performed to validate formulated tablets. We have maintained the acceptable official limits for weight variation, friability, hardness and disintegration time according to prescribed pharmacopoeial recommendation. In vitro drug release studies were performed using USP-II (paddle type) dissolution apparatus. The MTT assay was performed for assessment of Cell viability of drug combination for tablet formulation. Molecular docking studies have been performed to determine the combinatorial mode of action for the tablet formulation.Results: Friability and weight variation were less than 1% for each formulation, which were within range of prescribed pharmacopoeial recommendation. The hardness of 20 tablets showed 5-6.5Kg/cm2 for all formulations 5-6.5Kg/cm2. The optimized formulation resulted in 98% drug release after 28 h. The present study reports the synergistic effects of drug combination to inhibit cell growth in HepG2 cell line. Molecular docking studies showed that sorafenib has high binding affinity for B-Raf vascular endothelial growth factor receptor β and protein kinase B. Silibinin showed binding affinity with MAP kinase-11, protein phosphatase 2 A and tankyrase.Conclusion: The present study reports for the first time a novel formulation for sustained release and reduced toxicity of sorafenib with enhanced inhibitory effect of the drug combination on cancerous hepatic cell line as well collaborative mechanism of action for the formulation.

scholarly journals Rationale design and synthesis of some novel imidazole linked thiazolidinone hybrid molecules as DNA minor groove binders

2020 ◽  
Vol 11 (2) ◽  
pp. 120-132
Author(s):  
Javeed Ahmad War ◽  
Santosh Kumar Srivastava
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
Specific Binding ◽  
Minor Groove ◽  
Stable Complex ◽  
Binding Studies ◽  
In Vitro Susceptibility ◽  
Reference Drug ◽  
Hybrid Molecules

A new series of imidazole linked thiazolidinone hybrid molecules was designed and subsequently synthesized through a feasible, three step reaction protocol. The structures of these molecules were established using FT-IR, 1H NMR, 13C NMR and HRMS techniques. In vitro susceptibility tests against some Gram positive (Staphylococcus aureus and Bacillus subtilis) and Gram negative bacteria (Escherichia coli and Pseudomonas aeruginosa) exhibited broad spectrum potency of the molecules. The most potent molecule (S2A7) amongst the screened molecules, showed minimum inhibitory concentration (MIC) value not less than 2.0 µg/mL which was at par with the reference drug Streptomycin. Structure activity relationships revealed nitro and chloro groups being crucial for bioactivity when present at meta position of arylidene ring in 3-(3-(imidazol-1-yl)propyl)-5-(benzylidene)-2-(phenylimino)thiazolidin-4-one. Deoxyribonucleic acid (DNA)and bovine serum albumin (BSA) binding studies for S2A7 under simulated physiological pH were probed using UV-Visible, fluorescence quenching, gel electrophoresis and molecular docking techniques. These studies established that S2A7 has strong binding affinity towards DNA and binds at the minor groove of DNA with binding constant (Kb) of 0.1287×102 L/mol. Molecular docking simulations of S2A7 with DNA and BSA predicted binding affinity of -9.2 and -7.2 kcal/mol, respectively. Van der Waals forces and hydrogen bonding interactions were predicted as the main forces of interaction. With DNA, S2A7 exhibited specific binding affinity towards adenine-thiamine base pairs. The compound S2A7 forms a stable complex with BSA by binding at subdomain IIIA implying high bio-distribution of the compound.

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.

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