Repurposing anti-diabetic drugs for the treatment of Parkinson's disease: Rationale and clinical experience.

Prog Brain Res. 2020;252:493-523

Authors: Foltynie T, Athauda D

Abstract
The most pressing need in Parkinson's disease (PD) clinical practice is to identify agents that might slow down, stop or reverse the neurodegenerative process of Parkinson's disease and therefore avoid the onset of the most disabling, dopa-refractory symptoms of the disease. These include dementia, speech and swallowing problems, poor balance and falling. To date, there have been no agents which have yet had robust trial data to confirm positive effects at slowing down the neurodegenerative disease process of PD. In this chapter we will review the reasons why there is growing interest in drugs currently licensed for the treatment of diabetes as agents which may slow down disease progression in PD, including a review of the published trials regarding exenatide, a GLP-1 receptor agonist licensed to treat type 2 diabetes, and recently shown to be associated with reduced severity of PD in a randomized, placebo controlled washout design trial of 60 patients treated for 48 weeks. This subject is now a major area of interest for multiple pharmaceutical companies hoping to bring GLP-1 receptor agonists forward as treatment options in PD.

PMID: 32247373 [PubMed - indexed for MEDLINE]

Design, synthesis and anti-inflammatory activity of imidazol-5-yl pyridine derivatives as p38α/MAPK14 inhibitor.

Bioorg Med Chem. 2020 Dec 28;31:115969

Authors: Ali EMH, Abdel-Maksoud MS, Hassan RM, Mersal KI, Ammar UM, Se-In C, He-Soo H, Kim HK, Lee A, Lee KT, Oh CH

Abstract
P38α/MAPK14 is intracellular signalling regulator involved in biosynthesis of inflammatory mediator cytokines (TNF-α, IL-1, IL-6, and IL-1b), which induce the production of inflammatory proteins (iNOS, NF-kB, and COX-2). In this study, drug repurposing strategies were followed to repositioning of a series of B-RAF V600E imidazol-5-yl pyridine inhibitors to inhibit P38α kinase. A group 25 reported P38α kinase inhibitors were used to build a pharmacophore model for mapping the target compounds and proving their affinity for binding in P38α active site. Target compounds were evaluated for their potency against P38α kinase, compounds 11a and 11d were the most potent inhibitors (IC50 = 47 nM and 45 nM, respectively). In addition, compound 11d effectively inhibited the production of proinflammatory cytokinesTNF-α, 1L-6, and 1L-1β in LPS-induced RAW 264.7 macrophages with IC50 values of 78.03 nM, 17.6 µM and 82.15 nM, respectively. The target compounds were tested for their anti-inflammatory activity by detecting the reduction of Nitric oxide (NO) and prostaglandin (PGE2) production in LPS-stimulated RAW 264.7 macrophages. Compound 11d exhibited satisfied inhibitory activity of the production of PGE2 and NO with IC50 values of 0.29 µM and 0.61 µM, respectively. Molecular dynamics simulations of the most potent inhibitor 11d were carried out to illustrate its conformational stability in the binding site of P38α kinase.

PMID: 33422910 [PubMed - as supplied by publisher]

Network analysis and molecular mapping for SARS-CoV-2 to reveal drug targets and repurposing of clinically developed drugs.

Virology. 2020 Dec 30;555:10-18

Authors: More SA, Patil AS, Sakle NS, Mokale SN

Abstract
Novel coronavirus (SARS-CoV-2), turned out to be a global pandemic with unstoppable morbidity and mortality rate. However, till date there is no effective treatment found against SARS-CoV-2. We report on the major in-depth molecular and docking analysis by using antiretroviral (Lopinavir and ritonavir), antimalarial (Hydroxychloroquine), antibiotics (Azithromycin), and dietary supplements (Vitamin C and E) to provide new insight into drug repurposing molecular events involved in SARS-CoV-2. We constructed three drug-target-pathways-disease networks to predict the targets and drugs interactions as well as important pathways involved in SARS-CoV-2. The results suggested that by using the combination of Lopinavir, Ritonavir along with Hydroxychloroquine and Vitamin C may turned out to be the effective line of treatment for SARS-CoV-2 as it shows the involvement of PARP-1, MAPK-8, EGFR, PRKCB, PTGS-2, and BCL-2. Gene ontology biological process analysis further confirmed multiple viral infection-related processes (P < 0.001), including viral life cycle, modulation by virus, C-C chemokine receptor activity, and platelet activation. KEGG pathway analysis involves multiple pathways (P < 0.05), including FoxO, GnRH, ErbB, Neurotrophin, Toll-like receptor, IL-17, TNF, Insulin, HIF-1, JAK-STAT, Estrogen, NF-kappa, Chemokine, VEGF, and Thyroid hormone signaling pathway in SARS-CoV-2. Docking study was carried out to predict the molecular mechanism Thus, the potential drug combinations could reduce viral infectivity, viral replication, and abnormal host inflammatory responses and may be useful for multi-target drugs against SARS-CoV-2.

PMID: 33421743 [PubMed - as supplied by publisher]

ABBV-744 as a potential inhibitor of SARS-CoV-2 main protease enzyme against COVID-19.

Sci Rep. 2021 Jan 08;11(1):234

Authors: Fakhar Z, Khan S, AlOmar SY, Alkhuriji A, Ahmad A

Abstract
A new pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide and become pandemic with thousands new deaths and infected cases globally. To address coronavirus disease (COVID-19), currently no effective drug or vaccine is available. This necessity motivated us to explore potential lead compounds by considering drug repurposing approach targeting main protease (Mpro) enzyme of SARS-CoV-2. This enzyme considered to be an attractive drug target as it contributes significantly in mediating viral replication and transcription. Herein, comprehensive computational investigations were performed to identify potential inhibitors of SARS-CoV-2 Mpro enzyme. The structure-based pharmacophore modeling was developed based on the co-crystallized structure of the enzyme with its biological active inhibitor. The generated hypotheses were applied for virtual screening based PhaseScore. Docking based virtual screening workflow was used to generate hit compounds using HTVS, SP and XP based Glide GScore. The pharmacological and physicochemical properties of the selected lead compounds were characterized using ADMET. Molecular dynamics simulations were performed to explore the binding affinities of the considered lead compounds. Binding energies revealed that compound ABBV-744 binds to the Mpro with strong affinity (ΔGbind -45.43 kcal/mol), and the complex is more stable in comparison with other protein-ligand complexes. Our study classified three best compounds which could be considered as promising inhibitors against main protease SARS-CoV-2 virus.

PMID: 33420186 [PubMed - as supplied by publisher]

An Integrated In Silico and In Vivo Approach to Identify Protective Effects of Palonosetron in Cisplatin-Induced Nephrotoxicity.

Pharmaceuticals (Basel). 2020 Dec 20;13(12):

Authors: Wakai E, Suzumura Y, Ikemura K, Mizuno T, Watanabe M, Takeuchi K, Nishimura Y

Abstract
Cisplatin is widely used to treat various types of cancers, but it is often limited by nephrotoxicity. Here, we employed an integrated in silico and in vivo approach to identify potential treatments for cisplatin-induced nephrotoxicity (CIN). Using publicly available mouse kidney and human kidney organoid transcriptome datasets, we first identified a 208-gene expression signature for CIN and then used the bioinformatics database Cmap and Lincs Unified Environment (CLUE) to identify drugs expected to counter the expression signature for CIN. We also searched the adverse event database, Food and Drug Administration. Adverse Event Reporting System (FAERS), to identify drugs that reduce the reporting odds ratio of developing cisplatin-induced acute kidney injury. Palonosetron, a serotonin type 3 receptor (5-hydroxytryptamine receptor 3 (5-HT3R)) antagonist, was identified by both CLUE and FAERS analyses. Notably, clinical data from 103 patients treated with cisplatin for head and neck cancer revealed that palonosetron was superior to ramosetron in suppressing cisplatin-induced increases in serum creatinine and blood urea nitrogen levels. Moreover, palonosetron significantly increased the survival rate of zebrafish exposed to cisplatin but not to other 5-HT3R antagonists. These results not only suggest that palonosetron can suppress CIN but also support the use of in silico and in vivo approaches in drug repositioning studies.

PMID: 33419241 [PubMed - as supplied by publisher]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

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Int Immunopharmacol. 2021 Mar;92:107336. doi: 10.1016/j.intimp.2020.107336. Epub 2020 Dec 28.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) that has emerged and rapidly spread across the world. The COVID-19 severity is associated to viral pneumonia with additional extrapulmonary complications. Hyperinflammation, dysfunctional immune response and hypercoagulability state are associated to poor prognosis. Therefore, the repositioning of multi-target drugs to control the hyperinflammation represents an important challenge for the scientific community. Cilostazol, a selective phosphodiesterase type-3 inhibitor (PDE-3), is an antiplatelet and vasodilator drug, that presents a range of pleiotropic effects, such as antiapoptotic, anti-inflammatory, antioxidant, and cardioprotective activities. Cilostazol also can inhibit the adenosine uptake, which enhances intracellular cAMP levels. In the lungs, elevated cAMP promotes anti-fibrotic, vasodilator, antiproliferative effects, as well as mitigating inflammatory events. Interestingly, a recent study evaluated antiplatelet FDA-approved drugs through molecular docking-based virtual screening on viral target proteins. This study revealed that cilostazol is a promising drug against COVID-19 by inhibiting both main protease (Mpro) and Spike glycoprotein, reinforcing its use as a promising therapeutic approach for COVID-19. Considering the complexity associated to COVID-19 pathophysiology and observing its main mechanisms, this article raises the hypothesis that cilostazol may act on important targets in development of the disease. This review highlights the importance of drug repurposing to address such an urgent clinical demand safely, effectively and at low cost, reinforcing the main pharmacological actions, to support the hypothesis that a multi-target drug such as cilostazol could play an important role in the treatment of COVID-19.

PMID:33418248 | PMC:PMC7768212 | DOI:10.1016/j.intimp.2020.107336

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

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10 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2021/01/06

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9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2021/01/06

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2021/01/05

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7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

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Repositioning antispasmodic drug Papaverine for the treatment of chronic myeloid leukemia.

Pharmacol Rep. 2021 Jan 03;:

Authors: Parcha PK, Sarvagalla S, Ashok C, Sudharshan SJ, Dyavaiah M, Coumar MS, Rajasekaran B

Abstract
BACKGROUND: Papaverine is a benzylisoquinoline alkaloid from the plant Papaver somniferum (Opium poppy). It is approved as an antispasmodic drug by the US FDA and is also reported to have anti-cancer properties. Here, Papaverine's activity in chronic myeloid leukemia (CML) is explored using Saccharomyces cerevisiae, mammalian cancer cell lines, and in silico studies.
METHODS: The sensitivity of wild-type and mutant (anti-oxidant defense, apoptosis) strains of S. cerevisiae to the drug Papaverine was tested by colony formation, spot assays, and AO/EB staining. In vitro cytotoxic effect was investigated on HCT15 (colon), A549 (lung), HeLa (cervical), and K562 (Bcr-Abl positive CML), and RAW 264.7 cell lines; cell cycle, mitochondrial membrane potential, ROS detection analyzed in K562 cells using flow cytometry and apoptotic markers, Bcr-Abl signaling pathways examined by western blotting. Molecular docking and molecular dynamics simulation of Papaverine against the target Bcr-Abl were also carried out.
RESULTS: Investigation in S. cerevisiae evidenced Papaverine induces ROS-mediated apoptosis. Subsequent in vitro examination showed that CML cell line K562 was more sensitive to the drug Papaverine. Papaverine induces ROS generation, promotes apoptosis, and inhibits Bcr-Abl downstream signaling. Papaverine acts synergistically with the drug Imatinib. Furthermore, the docking and molecular dynamic simulation studies supported that Papaverine binds to the allosteric site of Bcr-Abl.
CONCLUSION: The data presented here have added support to the concept of polypharmacology of existing drugs and natural compounds to interact with more than one target. This study provides a proof-of-concept for repositioning Papaverine as an anti-CML drug.

PMID: 33389727 [PubMed - as supplied by publisher]

SARS-CoV-2 therapeutics: how far do we stand from a remedy?

Pharmacol Rep. 2021 Jan 03;:

Authors: Singh A, Gupta V

Abstract
The SARS-CoV-2 has affected millions worldwide and has posed an immediate need for effective pharmacological interventions. Ever since the outbreak was declared, the medical fraternity across the world is facing a unique situation of offering assistance and simultaneously generating reliable data with high-quality evidence to extend the scope of finding a treatment. With no proven vaccine or other interventions available hitherto, there is a frenzied urgency of sharing preliminary data from laboratories and trials to shape a global response against the virus. Several clinical trials with investigational and approved repurposed therapeutics have shown promising results. This review aims to compile the information of the reported molecules approved for emergency use and those under clinical trials and still others with good results in the studies conducted so far. Being an RNA virus, SARS-CoV-2 is prone to mutation; thus, the possibility of gaining resistance to available drugs is high. Consequently, a cocktail therapy based on drug interaction with different stages of its replicative cycle is desirable to reduce the chances of evolving drug resistance. Since this virus encodes several proteins, including 16 nonstructural and 4 structural proteins, this review also offers an insight into potential drug targets within SARS-CoV-2.

PMID: 33389724 [PubMed - as supplied by publisher]

The anti-HCV, Sofosbuvir, versus the anti-EBOV Remdesivir against SARS-CoV-2 RNA dependent RNA polymerase in silico.

Mol Divers. 2021 Jan 03;:

Authors: Elfiky AA, Azzam EB, Shafaa MW

Abstract
Coronavirus diseases 2019 (COVID-19) are seriously affecting human health all over the world. Nucleotide inhibitors have promising results in terms of its efficacy against different viral polymerases. In this study, detailed molecular docking and dynamics simulations are used to evaluate the binding affinity of a clinically approved drug, sofosbuvir, with the solved structure of the viral protein RNA-dependent RNA polymerase (RdRp) and compare it to the clinically approved drug, Remdesivir. These drugs are docked onto the three-dimensional structure of the nsp12 protein of SARS-CoV-2, which controls the polymerization process. Hence, it is considered one of the primary therapeutic targets for coronaviruses. Sofosbuvir is a drug that is currently used for HCV treatment; therefore, HCV RdRp is used as a positive control protein target. The protein dynamics are simulated for 100 ns, while the binding is tested during different dynamics states of the SARS-CoV-2 RdRp. Additionally, the drug-protein complexes are further simulated for 20 ns to explore the binding mechanism. The interaction of SARS-CoV-2 RdRp as a target with the active form of sofosbuvir as a ligand demonstrates binding effectiveness. One of the FDA-approved antiviral drugs, such as sofosbuvir, can help us in this mission, aiming to limit the danger of COVID-19. Sofosbuvir was found to bind nsp12 with comparable binding energies to that of Remdesivir, which has been reported for its potential against COVID-19 RdRp and is currently approved by the FDA.

PMID: 33389441 [PubMed - as supplied by publisher]

Culture of SARS-CoV-2 in a panel of laboratory cell lines, permissivity, and differences in growth profile.

Eur J Clin Microbiol Infect Dis. 2021 Jan 02;:

Authors: Wurtz N, Penant G, Jardot P, Duclos N, La Scola B

Abstract
The emergence of COVID-19 disease due to SARS-CoV-2 at the end of 2019 was rapidly associated with the isolation of the strain from co-culture onto VERO cells. These isolations quickly made it possible to carry out the first tests for antiviral agents' susceptibility and drug repurposing. However, it seems important to make an inventory of all the cells that can support the growth of this virus and evaluate possible differences between isolates. In the present work, we tested 4 strains of SARS-CoV-2 locally isolated on a panel of 34 cell lines present in our laboratory and commonly used for the isolation of human pathogenic microorganism. After inoculation, cells were observed for cytopathic effects and quantitative real-time polymerase reaction was used to measure the virus replication on the cells. We were able to obtain growth on 7 cell lines, 6 simian, and the human Caco-2. The cytopathogenic effects are variable, ranging from lysis of the cell monolayer in 48-72 h to no cytopathic effect in spite of intense multiplication, as in Caco-2 cells. Interestingly, effect and multiplication varied widely according to the strain tested. In this paper, we explored the species specificity and tissue tropism of SARS-CoV-2 in vitro on a panel of cells available in our laboratory and identified human and animal cell lines susceptible to support SARS-CoV-2 replication. Our work highlights the importance of testing multiple strains when testing antiviral molecules and performing patho-physiological analyzes.

PMID: 33389257 [PubMed - as supplied by publisher]

Overcoming barriers to implementing precision dosing with 5-Fluorouracil and capecitabine.

Br J Clin Pharmacol. 2021 Jan 02;:

Authors: Schneider JJ, Galettis P, Martin JH

Abstract
Despite advances in targeted cancer therapy, the fluoropyrimidines 5-fluorouracil (5FU) and capecitabine continue to play an important role in oncology. Historically, dosing of these drugs has been based on body surface area. This approach has been demonstrated to be an imprecise way to determine the optimal dose for a patient. Evidence in the literature has demonstrated that precision dosing approaches, such as DPD enzyme activity testing and, in the case of intravenous 5FU, pharmacokinetic guided dosing, can reduce toxicity and yield better patient outcomes. However, despite the evidence, there has not been uniform adoption of these approaches in the clinical setting. When a drug such as 5FU has been used clinically for many decades, it may be difficult to change clinical practice. With the aim of facilitating change of practice, issues and barriers to implementing precision dosing approaches for 5FU and capecitabine are identified and discussed with possible solutions proposed.

PMID: 33386659 [PubMed - as supplied by publisher]

Network machine learning maps phytochemically rich "Hyperfoods" to fight COVID-19.

Hum Genomics. 2021 Jan 02;15(1):1

Authors: Laponogov I, Gonzalez G, Shepherd M, Qureshi A, Veselkov D, Charkoftaki G, Vasiliou V, Youssef J, Mirnezami R, Bronstein M, Veselkov K

Abstract
In this paper, we introduce a network machine learning method to identify potential bioactive anti-COVID-19 molecules in foods based on their capacity to target the SARS-CoV-2-host gene-gene (protein-protein) interactome. Our analyses were performed using a supercomputing DreamLab App platform, harnessing the idle computational power of thousands of smartphones. Machine learning models were initially calibrated by demonstrating that the proposed method can predict anti-COVID-19 candidates among experimental and clinically approved drugs (5658 in total) targeting COVID-19 interactomics with the balanced classification accuracy of 80-85% in 5-fold cross-validated settings. This identified the most promising drug candidates that can be potentially "repurposed" against COVID-19 including common drugs used to combat cardiovascular and metabolic disorders, such as simvastatin, atorvastatin and metformin. A database of 7694 bioactive food-based molecules was run through the calibrated machine learning algorithm, which identified 52 biologically active molecules, from varied chemical classes, including flavonoids, terpenoids, coumarins and indoles predicted to target SARS-CoV-2-host interactome networks. This in turn was used to construct a "food map" with the theoretical anti-COVID-19 potential of each ingredient estimated based on the diversity and relative levels of candidate compounds with antiviral properties. We expect this in silico predicted food map to play an important role in future clinical studies of precision nutrition interventions against COVID-19 and other viral diseases.

PMID: 33386081 [PubMed - as supplied by publisher]

Integrated Analysis of Key Pathways and Drug Targets Associated With Vogt-Koyanagi-Harada Disease.

Front Immunol. 2020;11:587443

Authors: Chen Z, Zhong Z, Zhang W, Su G, Yang P

Abstract
Background: Vogt-Koyanagi-Harada (VKH) disease is a complex disease associated with multiple molecular immunological mechanisms. As the underlying mechanism for VKH disease is unclear, we hope to utilize an integrated analysis of key pathways and drug targets to develop novel therapeutic strategies.
Methods: Candidate genes and proteins involved in VKH disease were identified through text-mining in the PubMed database. The GO and KEGG pathway analyses were used to examine the biological functions of the involved pathways associated with this disease. Molecule-related drugs were predicted through Drug-Gene Interaction Database (DGIdb) analysis.
Results: A total of 48 genes and 54 proteins were associated with VKH disease. Forty-two significantly altered pathways were identified through pathway analysis and were mainly related to immune and inflammatory responses. The top five of significantly altered pathways were termed as "inflammatory bowel disease," "cytokine-cytokine receptor interaction," "allograft rejection," "antigen processing," and "presentation and Herpes simplex infection" in the KEGG database. IFN-γ and IL-6 were identified as the key genes through network analysis. The DGIdb analysis predicted 48 medicines as possible drugs for VKH disease, among which Interferon Alfa-2B was co-associated both with IFN-γ and IL-6.
Conclusions: In this study, systematic analyses were utilized to detect key pathways and drug targets in VKH disease via bioinformatics analysis. IFN-γ and IL-6 were identified as the key mediators and possible drug targets in VKH disease. Interferon Alfa-2B was predicted to be a potentially effective drug for VKH disease treatment by targeting IFN-γ and IL-6, which warrants further experimental and clinical investigations.

PMID: 33384687 [PubMed - in process]