scholarly journals Systematic Cell Line-Based Identification of Drugs Modifying ACE2 Expression

2020 ◽  
Author(s):  
Sanju Sinha ◽  
Kuoyuan Cheng ◽  
Kenneth Aldape ◽  
Eyal Schiff ◽  
Eytan Ruppin
Keyword(s):  
Ace Inhibitors ◽  
Angiotensin Receptor Blockers ◽  
Drug Effects ◽  
Cellular Protein ◽  
In Vivo Studies ◽  
Receptor Blockers ◽  
Approved Drugs ◽  
Vitamin A Derivative

The COVID-19 pandemic caused by SARS-COV-2 has infected over 500,000 people causing over 25,000 deaths in the last 10 weeks. A key host cellular protein required for the virus entry is angiotensin-converting enzyme 2 (ACE2). Recent studies have reported that patients with hypertension and diabetes treated with ACE inhibitors or angiotensin receptor blockers might be at a higher risk of COVID-19 infection as these drugs have been reported to increase ACE2 expression. This has raised the need to systematically investigate the effect of different drugs including antihypertensives on modulating ACE2 expression. Here, we analyzed a publicly available CMAP dataset of pre/post transcriptomic profiles for drug treatment in cell lines for over 20,000 small molecules. We show that only one subclass of antihypertensives drugs - ACE inhibitors, are significantly enriched for drugs up-regulating ACE2 expression. Studying the effects of the 672 clinically approved drugs in CMAP, we chart the drug categories that affect ACE2 expression. Specifically, we find that panobinostat (an HDAC inhibitor) confers the highest up-regulation of ACE2 expression while isotretinoin (a vitamin A derivative) is its strongest down-regulator. Our results provide initial candidates guiding further in vitro and in vivo studies aimed at assessing drug effects on ACE2 expression.

scholarly journals Inhibitory Perspective of New Synthesized Compounds against Angiotensin Receptor: Schrodinger-based Induced-Fit Molecular Docking

2021 ◽  
pp. 79-87
Author(s):  
Sethy Silky ◽  
Dhiman Neerupma ◽  
Garg Arun
Keyword(s):  
In Silico ◽  
Angiotensin Receptor Blockers ◽  
In Vivo Studies ◽  
Angiotensin Receptor ◽  
Standard Drug ◽  
Lipinski’S Rule ◽  
In Silico Study ◽  
Receptor Blockers

Angiotensin is a hormone that plays a key role in the development of hypertension. Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) are now the most often prescribed drugs to treat hypertension. The present in silico study involves exploring the antihypertensive potentials of substituted benzimidazoles and indazole compounds ARC 36, ARC 38, ARC 45, ARC 76, and ARC 77 against the most prominent molecular target Angiotensin Receptor (PDB ID: 4YAY, XFEL structure of Human Angiotensin Receptor)using the software Schrodinger Maestro .Based on glide score, ARC 45, ARC 76 and ARC77 were having the docking score of -7.461 Kcal/mol, -7.947 Kcal/mol and -6.683 Kcal/mol which is comparable to the standard drug (Telmisartan) -5.036.The compounds were further screened for Lipinski’s rule for drug-likeliness, and ADME properties. In this study we reported compounds ARC 76 and ARC38had comparable in silico parameters to the standard dug Telmisartan and hence necessitating further in vitro and in vivo studies.

Evaluation of Annona muricata (Graviola) leaves activity against experimental trichinellosis: in vitro and in vivo studies

2021 ◽  
Vol 95 ◽  
Author(s):  
E.S. El-Wakil ◽  
H.F. Abdelmaksoud ◽  
T.S. AbouShousha ◽  
M.M.I. Ghallab
Keyword(s):  
Culture Media ◽  
Trichinella Spiralis ◽  
Drug Effects ◽  
In Vivo Studies ◽  
Control Group ◽  
Annona Muricata ◽  
Group I ◽  
Small Intestinal

Abstract Our work aimed to evaluate the possible effect of Annona muricata (Graviola) leaf extract on Trichinella spiralis in in vitro and in vivo studies. Trichinella spiralis worms were isolated from infected mice and transferred to three culture media – group I (with no drugs), group II (contained Graviola) and group III (contained albendazole) – then they were examined using the electron microscope. In the in vivo study, mice were divided into five groups: GI (infected untreated), GII (prophylactically treated with Graviola for seven days before infection), GIII (infected and treated with Graviola), GIV (infected and treated with albendazole) and GV (infected and treated with a combination of Graviola plus albendazole in half doses). Drug effects were assessed by adults and larvae load beside the histopathological small intestinal and muscular changes. A significant reduction of adult and larval counts occurred in treated groups in comparison to the control group. Histopathologically, marked improvement in the small intestinal and muscular changes was observed in treated groups. Also, massive destruction of the cultured adults’ cuticle was detected in both drugs. This study revealed that Graviola leaves have potential activity against trichinellosis, especially in combination with albendazole, and could serve as an adjuvant to anti-trichinellosis drug therapy.

scholarly journals Tumour-on-chip microfluidic platform for assessment of drug pharmacokinetics and treatment response

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Tudor Petreus ◽  
Elaine Cadogan ◽  
Gareth Hughes ◽  
Aaron Smith ◽  
Venkatesh Pilla Reddy ◽  
...  
Keyword(s):  
Animal Studies ◽  
Drug Exposure ◽  
Drug Effects ◽  
Pharmacokinetic Profile ◽  
Microfluidic System ◽  
Drug Dose ◽  
In Vivo Studies ◽  
On Chip

AbstractMicrophysiological in vitro systems are platforms for preclinical evaluation of drug effects and significant advances have been made in recent years. However, existing microfluidic devices are not yet able to deliver compounds to cell models in a way that reproduces the real physiological drug exposure. Here, we introduce a novel tumour-on-chip microfluidic system that mimics the pharmacokinetic profile of compounds on 3D tumour spheroids to evaluate their response to the treatments. We used this platform to test the response of SW620 colorectal cancer spheroids to irinotecan (SN38) alone and in combination with the ATM inhibitor AZD0156, using concentrations mimicking mouse plasma exposure profiles of both agents. We explored spheroid volume and viability as a measure of cancer cells response and changes in mechanistically relevant pharmacodynamic biomarkers (γH2AX, cleaved-caspase 3 and Ki67). We demonstrate here that our microfluidic tumour-on-chip platform can successfully predict the efficacy from in vivo studies and therefore represents an innovative tool to guide drug dose and schedules for optimal efficacy and pharmacodynamic assessment, while reducing the need for animal studies.

scholarly journals Virtual Drug Repurposing Study Against SARS-CoV-2 TMPRSS2 Target

2020 ◽  
Author(s):  
Serdar Durdagi
Keyword(s):  
Clinical Investigation ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Positive Control ◽  
New Drugs ◽  
In Vivo Studies ◽  
Approved Drugs

<p>Currently, the world suffers from a new coronavirus SARS-CoV-2 that causes COVID-19. Therefore, there is a need for the urgent development of novel drugs and vaccines for COVID-19. Since it can take years to develop new drugs against this disease, here we used a hybrid combined molecular modeling approach in virtual drug screening repurposing study to identify new compounds against this disease. One of the important SARS-CoV-2 targets namely type 2 transmembrane serine protease (TMPRSS2) was screened with NPC’s NIH small molecule library which includes approved drugs by FDA and compounds in clinical investigation. We used 6654 small molecules in molecular docking and top-50 docking scored compounds were initially used in short (10-ns) molecular dynamics (MD) simulations. Based on average MM/GBSA binding free energy results, long (100-ns) MD simulations were employed for the identified hits. Both binding energy results as well as crucial residues in ligand binding were also compared with a positive control TMPRSS2 inhibitor, Camostat mesylate. Based on these numerical calculations we proposed a compound (benzquercin) as strong TMPRSS2 inhibitor. If these results can be validated by in vitro and in vivo studies, benzquercin can be considered to be used as inhibitor of TMPRSS2 at the clinical studies.</p>

scholarly journals Losartan Improves Memory, Neurogenesis and Cell Motility in Transgenic Alzheimer’s Mice

2021 ◽  
Vol 14 (2) ◽  
pp. 166
Author(s):  
Henning Johannes Drews ◽  
Roman Klein ◽  
Ali Lourhmati ◽  
Marine Buadze ◽  
Elke Schaeffeler ◽  
...  
Keyword(s):  
Cell Motility ◽  
Angiotensin Receptor Blockers ◽  
Intraperitoneal Administration ◽  
Beneficial Effects ◽  
Receptor Blockers ◽  
Delivery Route ◽  
Interstudy Variability ◽  
New Strategies

Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer’s disease (AD) models. However, their beneficial effects on memory deficits, cholinergic activity, neurogenesis and Amyloid beta (Aβ) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also targeting and therapeutic efficacy of ARBs. Our previous findings on the beneficial effects of intranasally delivered losartan in the APP/PS1 model of AD prompted us to explore the influence of the delivery route by employing here the systemic administration of losartan. Consistent with our previous results with intranasal losartan, repeated intraperitoneal administration (10 mg/kg) resulted in a remarkable decrease in Aβ plaques and soluble Aβ42, as well as inflammatory cytokines (IL-2, IL-6 and TNFα). The Aβ reduction can be ascribed to its facilitated degradation by neprilysin and diminished generation by BACE1. Losartan increased neurogenesis in vivo and in vitro and improved migratory properties of astrocytes isolated from adult transgenic AD mice. In summary, this data together with our previous results suggest therapeutic features of losartan which are independent of delivery route. The improvement of cell motility of Aβ-affected astrocytes by losartan deserves further in vivo investigation, which may lead to new strategies for AD treatment.

scholarly journals From Xanthine Oxidase Inhibition to In Vivo Hypouricemic Effect: An Integrated Overview of In Vitro and In Vivo Studies with Focus on Natural Molecules and Analogues

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
João L. Serrano ◽  
Joana Figueiredo ◽  
Paulo Almeida ◽  
Samuel Silvestre
Keyword(s):  
Xanthine Oxidase ◽  
Animal Studies ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Pharmacodynamic Profile ◽  
Xanthine Oxidase Inhibition ◽  
The Moment ◽  
Approved Drugs

Hyperuricemia is characterized by elevated uric acid (UA) levels on blood, which can lead to gout, a common pathology. These high UA levels are associated with increased purine ingestion and metabolization and/or its decreased excretion. In this field, xanthine oxidase (XO), by converting hypoxanthine and xanthine to UA, plays an important role in hyperuricemia control. Based on limitations and adverse effects associated with the use of allopurinol and febuxostat, the most known approved drugs with XO inhibitory effect, the search for new molecules with XO activity is growing. However, despite the high number of studies, it was found that the majority of tested products with relevant XO inhibition were left out, and no further pharmacological evaluation was performed. Thus, in the present review, available information published in the past six years concerning isolated molecules with in vitro XO inhibition complemented with cytotoxicity evaluation as well as other relevant studies, including in vivo hypouricemic effect, and pharmacokinetic/pharmacodynamic profile was compiled. Interestingly, the analysis of data collected demonstrated that molecules from natural sources or their mimetics and semisynthetic derivatives constitute the majority of compounds being explored at the moment by means of in vitro and in vivo animal studies. Therefore, several of these molecules can be useful as lead compounds and some of them can even have the potential to be considered in the future clinical candidates for the treatment of hyperuricemia.

scholarly journals Pharmacophore Investigations of Potential COVID-19 RNA Polymerase (Rdrp) Inhibitors: Repurposing FDA-Approved Drugs

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Valentina L. Kouznetsova ◽  
Caroline Kellogg ◽  
Aidan Zhang ◽  
Mahidhar Tatineni ◽  
Mark A. Miller ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Hydrophobic Interactions ◽  
Pharmacophore Model ◽  
In Vivo Studies ◽  
Drug Candidates ◽  
Promising Target ◽  
Approved Drugs ◽  
Fda Approved Drugs

Authors: Valentina L. Kouznetsova, Caroline Kellogg, Aidan Zhang, Mahidhar Tatineni, Mark A. Miller, Igor F. Tsigelny Background: SARS-CoV-2 has caused tens of millions of infections worldwide and millions of deaths. Currently, no effective treatment has been identified against the virus. Of its viral proteins, the RNA-dependent RNA polymerase (RdRp) is a promising target for drug design because of its importance in the replication of the virus. Material and Methods: After the identification of an RdRp pocket site based on the crystal structure of the RdRp– nsp7–nsp8 complex and the triphosphate form of remdesivir (PDB ID: 7BV2), we created a pharmacophore model consisting of 11 different features. These features include two acceptors, three donors, one acceptor and donor, three donor or acceptor, and one hydrophobic; an excluded volume of R=1.1 Å was also added. We then ran a pharmacophore search on our conformational database (DB) of approximately 2500 FDA-approved drugs and 600 000 conformations to identify potential drug-candidates. To determine the drugs that bound the best, we conducted multi conformational docking of these results to the previously identified pocket site. Results: The pharmacophore search found 315 different potential inhibitors of RdRp, of which 85 were chosen based on the number of H-bonds and hydrophobic interactions in the best docking pose. Several of the drugs selected, including ritonavir, dasatinib, imatinib, and sofosbuvir, have previously been shown to be effective against other viruses. Conclusions: These findings highlight compounds that could lead to both in vitro and in vivo studies to identify potential treatments against SARS-CoV-2.

scholarly journals Assessment of FDA-approved drugs against Strongyloides ratti in vitro and in vivo to identify potentially active drugs against strongyloidiasis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jennifer Keiser ◽  
Cécile Häberli
Keyword(s):  
Gentian Violet ◽  
Cetylpyridinium Chloride ◽  
Drug Repurposing ◽  
Strongyloides Stercoralis ◽  
In Vivo Studies ◽  
Benzethonium Chloride ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract Background Infections with Strongyloides stercoralis belong to the most neglected helminth diseases, and research and development (R&D) efforts on novel drugs are inadequate. Methods A commercially available library containing 1600 FDA-approved drugs was tested in vitro against Strongyloides ratti larvae (L3) at 100 µM. Hits (activity > 70%) were then evaluated against S. ratti adult worms at 10 µM. Morantel, prasterone, and levamisole were tested in the S. ratti rat model using dosages of 1–100 mg/kg. Results Seventy-one of the 1600 compounds tested against S. ratti L3 revealed activity above 70%. Of 64 compounds which progressed into the adult screen, seven compounds achieved death of all worms (benzethonium chloride, cetylpyridinium chloride, Gentian violet, methylbenzethonium chloride, morantel citrate, ivermectin, coumaphos), and another eight compounds had activity > 70%. Excluding topical and toxic compounds, three drugs progressed into in vivo studies. Prasterone lacked activity in vivo, while treatment with 100 mg/kg morantel and levamisole cured all rats. The highest in vivo activity was observed with levamisole, yielding a median effective dose (ED50) of 1.1 mg/kg. Conclusions Using a drug repurposing approach, our study identified levamisole as a potential backup drug for strongyloidiasis. Levamisole should be evaluated in exploratory clinical trials. Graphical Abstract

scholarly journals Virtual Drug Repurposing Study Against SARS-CoV-2 TMPRSS2 Target

2020 ◽  
Author(s):  
Serdar Durdagi
Keyword(s):  
Clinical Investigation ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Positive Control ◽  
New Drugs ◽  
In Vivo Studies ◽  
Approved Drugs

<p>Currently, the world suffers from a new coronavirus SARS-CoV-2 that causes COVID-19. Therefore, there is a need for the urgent development of novel drugs and vaccines for COVID-19. Since it can take years to develop new drugs against this disease, here we used a hybrid combined molecular modeling approach in virtual drug screening repurposing study to identify new compounds against this disease. One of the important SARS-CoV-2 targets namely type 2 transmembrane serine protease (TMPRSS2) was screened with NPC’s NIH small molecule library which includes approved drugs by FDA and compounds in clinical investigation. We used 6654 small molecules in molecular docking and top-50 docking scored compounds were initially used in short (10-ns) molecular dynamics (MD) simulations. Based on average MM/GBSA binding free energy results, long (100-ns) MD simulations were employed for the identified hits. Both binding energy results as well as crucial residues in ligand binding were also compared with a positive control TMPRSS2 inhibitor, Camostat mesylate. Based on these numerical calculations we proposed a compound (benzquercin) as strong TMPRSS2 inhibitor. If these results can be validated by in vitro and in vivo studies, benzquercin can be considered to be used as inhibitor of TMPRSS2 at the clinical studies.</p>

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