scholarly journals Molecular Docking and Admet Analyses of Photochemicals from Nigella sativa (blackseed), Trigonella foenum-graecum (Fenugreek) and Anona muricata (Soursop) on SARS-CoV-2 Target

2020 ◽  
Author(s):  
OLUWASEUN TAOFEEK
Keyword(s):  
Molecular Docking ◽  
Electrostatic Interactions ◽  
Nigella Sativa ◽  
Critical Role ◽  
In Vivo Studies ◽  
Viral Gene ◽  
Discovery Studio ◽  
Trigonella Foenum Graecum

The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) responsible for the 2019 coronavirus disease (COVID-19) has caused a global health challenge. The SARS-COV-2 main protease, 3CLpro/Mpro plays a critical role in the viral gene expression and replication and has been a major target for inhibiting viral maturation and enhancing host innate immune responses against COVID-19. In this study, we screened a library of 38 phytochemicals from Nigella sativa (blackseed), Trigonella foenum-graecum (Fenugreek) and Anona muricata (Soursop) potent medicinal plants with reported antiviral properties - in a molecular docking protocol on 3CLpro using Autodock4.0 tool implanted in PyRx followed by docking validation and insilico absorption, distribution, metabolism, excretion, and toxicology (ADMET) evaluations. The docking results were visualized using Accelrys Discovery Studio and Pymol software. Among the 38 ligands screened, 19 showed significant interaction through non-covalent hydrogen bonding, hydrophobic, and electrostatic interactions with binding affinities from -5.3kcal/mol to -8.1kcal/mol indicating significant binding interactions at the active site binding pocket. Another important interaction observed in the study which mostly involve the transfer of charges was pi-interactions such as Pi-Pi interaction, Pi-Alkyl interaction, Pi-Sulfur interaction, Pi- Sigma, and Pi-Pi stacking. The docking results revealed that phytochemicals from T. foenum-graecum showed more 3CLpro inhibitory potential compared to those from N. sativa and A. muricata. Insilico ADMET evaluations for drug-like and lead-like characteristics however demonstrated that only 8 ligands - apigenin, kaempferol, luteolin, dithymoquinone, naringenine, nornuciferine, quercetin and nigellidine were actually drug-like; showed best activities against 3CLpro, and lack hepatotoxicity effects while none was lead-like. Insilico results of this study further suggested that drug repurposing candidates, remdesivir, indinavir,hydroxychloroquine, chloroquine and ritonavir,exhibited various interactions with 3CLpro. Hence, further in vitro and in vivo studies are proposed.

Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-216469
Author(s):  
Alison W Ha ◽  
Tao Bai ◽  
David L Ebenezer ◽  
Tanvi Sethi ◽  
Tara Sudhadevi ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lysyl Oxidase ◽  
Critical Role ◽  
Sphingosine Kinase ◽  
In Vivo Studies ◽  
Sphingosine Kinase 1 ◽  
Neonatal Lung ◽  
Neonatal Lung Injury

IntroductionNeonatal lung injury as a consequence of hyperoxia (HO) therapy and ventilator care contribute to the development of bronchopulmonary dysplasia (BPD). Increased expression and activity of lysyl oxidase (LOX), a key enzyme that cross-links collagen, was associated with increased sphingosine kinase 1 (SPHK1) in human BPD. We, therefore, examined closely the link between LOX and SPHK1 in BPD.MethodThe enzyme expression of SPHK1 and LOX were assessed in lung tissues of human BPD using immunohistochemistry and quantified (Halo). In vivo studies were based on Sphk1−/− and matched wild type (WT) neonatal mice exposed to HO while treated with PF543, an inhibitor of SPHK1. In vitro mechanistic studies used human lung microvascular endothelial cells (HLMVECs).ResultsBoth SPHK1 and LOX expressions were increased in lungs of patients with BPD. Tracheal aspirates from patients with BPD had increased LOX, correlating with sphingosine-1-phosphate (S1P) levels. HO-induced increase of LOX in lungs were attenuated in both Sphk1−/− and PF543-treated WT mice, accompanied by reduced collagen staining (sirius red). PF543 reduced LOX activity in both bronchoalveolar lavage fluid and supernatant of HLMVECs following HO. In silico analysis revealed STAT3 as a potential transcriptional regulator of LOX. In HLMVECs, following HO, ChIP assay confirmed increased STAT3 binding to LOX promoter. SPHK1 inhibition reduced phosphorylation of STAT3. Antibody to S1P and siRNA against SPNS2, S1P receptor 1 (S1P1) and STAT3 reduced LOX expression.ConclusionHO-induced SPHK1/S1P signalling axis plays a critical role in transcriptional regulation of LOX expression via SPNS2, S1P1 and STAT3 in lung endothelium.

scholarly journals STRUCTURE-BASED MULTITARGETED MOLECULAR DOCKING ANALYSIS OF PYRAZOLE-CONDENSED HETEROCYCLICS AGAINST LUNG CANCER

2021 ◽  
pp. 157-169
Author(s):  
JAINEY P. JAMES ◽  
AISWARYA T. C. ◽  
SNEH PRIYA ◽  
DIVYA JYOTHI ◽  
SHESHAGIRI R. DIXIT
Keyword(s):  
Lung Cancer ◽  
Molecular Docking ◽  
Binding Mode ◽  
Pharmacophore Modeling ◽  
In Vivo Studies ◽  
Spectral Studies ◽  
Pyrazole Derivatives ◽  
Anticancer Activities

Objective: The significant drawbacks of chemotherapy are that it destroys healthy cells, resulting in adverse effects. Hence, there is a need to adopt new techniques to develop cancer-specific chemicals that target the molecular pathways in a non-toxic fashion. This study aims to screen pyrazole-condensed heterocyclics for their anticancer activities and analyse their enzyme inhibitory potentials EGFR, ALK, VEGFR and TNKS receptors. Methods: The structures of the compounds were confirmed by IR, NMR and Mass spectral studies. The in silico techniques applied in this study were molecular docking and pharmacophore modeling to analyse the protein-ligand interactions, as they have a significant role in drug discovery. Drug-likeness properties were assessed by the Lipinski rule of five and ADMET properties. Anticancer activity was performed by in vitro MTT assay on lung cancer cell lines. Results: The results confirm that all the synthesised pyrazole derivatives interacted well with the selected targets showing docking scores above-5 kcal/mol. Pyrazole 2e interacted well with all the four lung cancer targets with its stable binding mode and was found to be potent as per the in vitro reports, followed by compounds 3d and 2d. Pharmacophore modeling exposed the responsible features responsible for the anticancer action. ADMET properties reported that all the compounds were found to have properties within the standard limit. The activity spectra of the pyrazoles predicted that pyrazolopyridines (2a-2e) are more effective against specific receptors such as EGFR, ALK and Tankyrase. Conclusion: Thus, this study suggests that the synthesised pyrazole derivatives can be further investigated to validate their enzyme inhibitory potentials by in vivo studies.

scholarly journals Effect of Harmine against Parkinson’s Disease Protein (PARK7) through Molecular Docking Studies

2021 ◽  
Vol 9 (VI) ◽  
pp. 5479-5485
Author(s):  
Love Kumar
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Docking ◽  
Neurodegenerative Disorder ◽  
Docking Studies ◽  
In Vivo Studies ◽  
Receptor Protein ◽  
Unknown Etiology

Parkinson’s disease (PD) is a common known neurodegenerative disorder with unknown etiology. It was estimated about 0.3% prevalence in the U.S population and enhance to 4 to 5% in older than 85 years. All studies were depending on the molecular docking where all ligands and protein PARK7 (PDB ID: 2RK3) were interacted by docked process. Some natural compounds was selected such as Harmine, Alloxan, Alpha spinasterol, Myrcene, and Vasicinone and PARK7 (PDB ID: 2RK3) protein. According to the PyRx and SWISS ADME result, Harmine was the only ligand which was showing minimum binding affinity. AutoDock Vina software was used for docking process between ligand (Harmine) and receptor protein PARK7 (PDB ID: 2RK3). The result was visualized under PyMol. Harmine was inhibiting the activity of PARK7 (PDB ID: 2RK3) and it may be used for the treatment of PD in future prospect after its in vitro and in vivo studies.

Neuroprotective effects of bergenin in Alzheimer’s disease: Investigation through molecular docking, in vitro and in vivo studies

2019 ◽  
Vol 356 ◽  
pp. 18-40 ◽  
Author(s):  
Priyal Barai ◽  
Nisith Raval ◽  
Sanjeev Acharya ◽  
Ankit Borisa ◽  
Hardik Bhatt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Docking ◽  
In Vivo Studies ◽  
Neuroprotective Effects

scholarly journals THE POTENTIAL OF ROBUSTA COFFEE (COFFEA CANEPHORA) AS A COLORECTAL CANCER THERAPY MODALITY: AN IN SILICO STUDY

2021 ◽  
pp. 83-87
Author(s):  
DESSY AGUSTINI ◽  
LEO VERNADESLY ◽  
DELVIANA ◽  
THEODORUS
Keyword(s):  
Colorectal Cancer ◽  
In Silico ◽  
Hydrophobic Interactions ◽  
Binding Energies ◽  
In Vivo Studies ◽  
Discovery Studio ◽  
Robusta Coffee ◽  
In Silico Study

Objectives: This research aims to determine the efficacy of compounds in robusta coffee against colorectal cancer through the inhibition of the T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) receptor. Methods: This in silico study has been conducted in computing platform from June to August 2021. The selected test compounds would go through the Lipinski rule screening through the SwissADME website and the compounds that met these regulations would be docked to the TIGIT protein using AutoDock Tools and AutoDock Vina. The interactions with the highest binding energies were visualized using BIOVIA Discovery Studio 2020. The test compounds then underwent a toxicity profile analysis on the admetSAR 2.0 website. Results: All test compounds complied with the Lipinski rule. The molecular docking results showed the highest binding energy in kahweol and cafestol (−8.1 kcal/mol) compared to OMC (−7.9 kcal/mol), chlorogenic acid (−7.8 kcal/mol), caffeic acid (−6.3 kcal/mol), caffeine (−6.1 kcal/mol), trigonelline (−5.3 kcal/mol), HMF (−5.1 kcal/mol), furfuryl alcohol (−4.4 kcal/mol), and 5-fluorouracil as the comparator drug (−5.3 kcal/mol). Kahweol, cafestol, and 5-fluorouracil revealed the hydrophobic interactions and hydrogen bonds with amino acid residues in TIGIT. Kahweol and cafestol unveiled minimal toxicity prediction Conclusion: Kahweol and cafestol demonstrated the best results in inhibiting the TIGIT protein which played a role in colorectal cancer. In vitro and in vivo studies are needed to strengthen the findings of this research.

scholarly journals Preliminary Study on the Effect of Quinolone against Rec A Protein for the Possible Role in the Treatment of Tuberculosis through Molecular Docking

2021 ◽  
Vol 9 (VII) ◽  
pp. 227-232
Author(s):  
Priyanka Gautam
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Chronic Disease ◽  
In Vivo Studies ◽  
Online Database ◽  
Docking Method ◽  
Preliminary Study ◽  
Molecular Docking Method

Tuberculosis is a type of ancient, chronic disease which affects humans and caused by Mycobacterium tuberculosis. They affect the lungs and other organs. The treatment is curable but in some cases it is fatal if not treated properly. The molecular docking method was used to see the interaction of the protein with the ligand. Thus, molecular docking was used to analyse the Rec A (PDB ID 1U94) target protein with their known type of ligand by using molecular docking tools. The Rec A (PDB ID 1U94) structure of protein was downloaded through online database. The best ligand after molecular docking was Quinolone, which may act as a drug after in vitro and in vivo studies.

scholarly journals Impaired Brain Mitochondrial Bioenergetics in the Ts65Dn Mouse Model of Down Syndrome Is Restored by Neonatal Treatment with the Polyphenol 7,8-Dihydroxyflavone

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 62
Author(s):  
Daniela Valenti ◽  
Fiorenza Stagni ◽  
Marco Emili ◽  
Sandra Guidi ◽  
Renata Bartesaghi ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Critical Role ◽  
Hippocampal Neurogenesis ◽  
In Vivo Studies ◽  
Mitochondrial Bioenergetics ◽  
Ts65dn Mouse ◽  
Atp Production

Down syndrome (DS), a major genetic cause of intellectual disability, is characterized by numerous neurodevelopmental defects. Previous in vitro studies highlighted a relationship between bioenergetic dysfunction and reduced neurogenesis in progenitor cells from the Ts65Dn mouse model of DS, suggesting a critical role of mitochondrial dysfunction in neurodevelopmental alterations in DS. Recent in vivo studies in Ts65Dn mice showed that neonatal supplementation (Days P3–P15) with the polyphenol 7,8-dihydroxyflavone (7,8-DHF) fully restored hippocampal neurogenesis. The current study was aimed to establish whether brain mitochondrial bioenergetic defects are already present in Ts65Dn pups and whether early treatment with 7,8-DHF positively impacts on mitochondrial function. In the brain and cerebellum of P3 and P15 Ts65Dn pups we found a strong impairment in the oxidative phosphorylation apparatus, resulting in a deficit in mitochondrial ATP production and ATP content. Administration of 7,8-DHF (dose: 5 mg/kg/day) during Days P3–P15 fully restored bioenergetic dysfunction in Ts65Dn mice, reduced the levels of oxygen radicals and reinstated the hippocampal levels of PGC-1α. No pharmacotherapy is available for DS. From current findings, 7,8-DHF emerges as a treatment with a good translational potential for improving mitochondrial bioenergetics and, thus, mitochondria-linked neurodevelopmental alterations in DS.

Circulating CD62E Occurs in Soluble Form as Well as Bound to Endothelial Microparticles (EMP): Functional Differences in Platelet Aggregation in Thrombotic Thrombocytopenic Purpura (TTP).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2624-2624
Author(s):  
Joaquin J. Jimenez ◽  
Wenche Jy ◽  
Lucia M. Mauro ◽  
Michael N. Markou ◽  
George W. Burke ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Endothelial Cells ◽  
Platelet Aggregation ◽  
Acute Phase ◽  
Critical Role ◽  
In Vivo Studies ◽  
Soluble Form ◽  
Dependent Manner

Abstract Injured endothelial cells (EC) are believed to play a critical role in the pathophysiology of TTP. Soluble markers of endothelial disturbance measured by enzyme-linked immunoassay (ELISA) have been found elevated in TTP. We have recently demonstrated an increase in the release of CD31/42b- EMP, and CD62E+ EMP. Moreover, we have observed that CD62E+ EMP also express vWF. The aim of this study was to quantitate soluble (s) vs. EMP-bound CD62E (bCD62E) in vitro and in vivo, in relation to the functional activity of vWF+ EMP. METHODS: Brain and renal microvascular endothelial cells (MVEC) were cultured and treated with 10ng/mL TNF-α to induce activation, or deprived of serum and growth factors (GFD) to induce apoptosis. Culture supernatants were collected and evaluated in a time-dependent manner. For in vivo studies, platelet-poor plasma was obtained from 4 TTP patients during the acute phase and upon remission. Filtration through 0.1μm, which retains most EMP, was employed to discriminate between (s) and bCD62E. sCD62E was measured by ELISA post-filtration and bCD62E by ELISA pre-filtration. Additionally, CD62E+ and CD62E+/vWF+ EMP were measured by flow cytometry. To assess pro-aggregatory function, EMP were added to washed platelets in the presence of 1 mg/mL ristocetin and aggregates were measured by flow cytometry. RESULTS: In vitro: Activation did not induce release of sCD62E at 3 hours, although bCD62E was present (1.5±0.5X106 EMP/mL). At 6 hours, some sCD62E was detected in the filtrate (0.09±0.02 ng/mL), but most was present in the unfiltered medium (3.5±0.85 ng/mL), signifying that the majority was bCD62E, confirmed by a doubling of CD62E+ EMP (3.0±0.6X106/mL). Subsequently, sCD62E levels were 1.0±0.2 ng/mL at 12 hr, 3.5±0.7 ng/mL at 18 hr, and 5±0.9 ng/mL at 24 hr. In contrast, EMP counts at 12, 18 and 24 hours were 4.6±1, 7±1.3 and 9±1.8 X106/mL (p=0.01, p=0.01, p=0.02, respectively). For all time periods, 40-60% of CD62E were positive for vWF. In control or GFD cultures, there was not a significant increase in sCD62E or CD62E+ EMP at any time period. MVEC from renal gave similar results. In acute TTP plasma samples, CD62E measured by ELISA was significantly increased (65±22 ng/mL) vs. remission (30±6 ng/mL). bCD62E accounted for 50% in acute and 15% in remission. CD62E+/vWF+ EMP were significantly elevated in plasma from acute TTP patients vs. remission (15±4.5 vs. 3±0.5, p=0.01). Sample filtration resulted in a decrease of >95% EMP in both acute and remission TTP plasma. MVEC-derived CD62E+/vWF+ EMP resulted in a dose-dependent increase in platelet aggregation. Additionally, plasma from 4 TTP patients with elevated CD62E+/vWF+ EMP obtained during the acute phase enhanced the formation of platelet aggregates by 48±12% (p=0.02) above remission plasma with low EMP counts. CONCLUSIONS: The results demonstrate that CD62E heretofore regarded as a soluble marker of endothelial dysfunction, in reality exists in both a soluble and EMP-bound form. Indeed, this distinction is highly relevant because CD62E+ EMP also express vWF and are pro-aggregatory to platelets. These EMP have been shown to be elevated during the acute phase of TTP and decrease upon remission. Thus, CD62E+/vWF+ EMP may be active participants in the formation of platelet-rich thrombi in TTP.

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