From Anti-infective Agents to Cancer Therapy: a Drug Repositioning Study Revealed a New Use for Nitrofuran Derivatives

Background: The progression of ovarian cancer seems to be related to HDAC1, HDAC3 and HDAC6 activity. A possible strategy for improving therapies for treating ovarian carcinoma, minimizing the preclinical screenings, is the repurposing of already approved pharmaceutical products as inhibitors of these enzymes. Objective: This work was aimed to implement a computational strategy for identifying new HDAC inhibitors for ovarian carcinoma treatment among approved drugs. Method: The CHEMBL database was used to construct training, test and decoys sets for performing and validating HDAC1, HDAC3 and HDAC6 3D-QSAR models obtained by using FLAP program. Docking and MD simulations were used in combination with the generated models to identify novel potential HDAC inhibitors. Cell viability assays and Western blot analyses were performed on normal and cancer cells for a direct evaluation of the anti-proliferative activity and an in vitro estimation of HDAC inhibition of the compounds selected through in silico screening. Result: The best quantitative prediction was obtained for the HDAC6 3D-QSAR model. The screening of approved drugs highlighted a new potential use as HDAC inhibitors for some compounds, in particular nitrofuran derivatives, usually known for their antibacterial activity, and frequently used as antimicrobial adjuvant therapy in cancer treatment. Experimental evaluation of these derivatives highlighted a significant antiproliferative activity against cancer cell lines overexpressing HDAC6, and an increase in acetylated alpha-tubulin levels. Conclusion: Experimental results support the hypothesis of a potential direct interaction of nitrofuran derivatives with HDACs. In addition to the possible repurposing of already approved drugs, this work suggests the nitro group as a new zinc binding group, able to interact with the catalytic zinc ion of HDACs.

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Targeting SARS-CoV-2 Polymerase with New Nucleoside Analogues

Molecules ◽

10.3390/molecules26113461 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3461

Author(s):

Vasiliki Daikopoulou ◽

Panagiotis Apostolou ◽

Sofia Mourati ◽

Ioanna Vlachou ◽

Maria Gougousi ◽

...

Keyword(s):

Inhibitory Activity ◽

Drug Repositioning ◽

Nucleoside Analogues ◽

In Vitro Assays ◽

Rna Dependent Rna Polymerase ◽

Sugar Moiety ◽

The Family ◽

Approved Drugs ◽

Fda Approved Drugs

Despite the fact that COVID-19 vaccines are already available on the market, there have not been any effective FDA-approved drugs to treat this disease. There are several already known drugs that through drug repositioning have shown an inhibitory activity against SARS-CoV-2 RNA-dependent RNA polymerase. These drugs are included in the family of nucleoside analogues. In our efforts, we synthesized a group of new nucleoside analogues, which are modified at the sugar moiety that is replaced by a quinazoline entity. Different nucleobase derivatives are used in order to increase the inhibition. Five new nucleoside analogues were evaluated with in vitro assays for targeting polymerase of SARS-CoV-2.

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Lapatinib, Nilotinib and Lomitapide Inhibit Haemozoin Formation in Malaria Parasites

Molecules ◽

10.3390/molecules25071571 ◽

2020 ◽

Vol 25 (7) ◽

pp. 1571 ◽

Cited By ~ 2

Author(s):

Ana Carolina C. de Sousa ◽

Keletso Maepa ◽

Jill M. Combrinck ◽

Timothy J. Egan

Keyword(s):

Experimental Evaluation ◽

Antimalarial Activity ◽

Drug Repositioning ◽

Hit Rate ◽

Docking Method ◽

Electrostatic Similarity ◽

Approved Drugs ◽

Novel Structures ◽

Antimalarial Action

With the continued loss of antimalarials to resistance, drug repositioning may have a role in maximising efficiency and accelerating the discovery of new antimalarial drugs. Bayesian statistics was previously used as a tool to virtually screen USFDA approved drugs for predicted β-haematin (synthetic haemozoin) inhibition and in vitro antimalarial activity. Here, we report the experimental evaluation of nine of the highest ranked drugs, confirming the accuracy of the model by showing an overall 93% hit rate. Lapatinib, nilotinib, and lomitapide showed the best activity for inhibition of β-haematin formation and parasite growth and were found to inhibit haemozoin formation in the parasite, providing mechanistic insights into their mode of antimalarial action. We then screened the USFDA approved drugs for binding to the β-haematin crystal, applying a docking method in order to evaluate its performance. The docking method correctly identified imatinib, lapatinib, nilotinib, and lomitapide. Experimental evaluation of 22 of the highest ranked purchasable drugs showed a 24% hit rate. Lapatinib and nilotinib were chosen as templates for shape and electrostatic similarity screening for lead hopping using the in-stock ChemDiv compound catalogue. The actives were novel structures worthy of future investigation. This study presents a comparison of different in silico methods to identify new haemozoin-inhibiting chemotherapeutic alternatives for malaria that proved to be useful in different ways when taking into consideration their strengths and limitations.

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Drug repositioning of Clopidogrel or Triamterene to inhibit influenza virus replication in vitro

PLoS ONE ◽

10.1371/journal.pone.0259129 ◽

2021 ◽

Vol 16 (10) ◽

pp. e0259129

Author(s):

Nichole Orr-Burks ◽

Jackelyn Murray ◽

Kyle V. Todd ◽

Abhijeet Bakre ◽

Ralph A. Tripp

Keyword(s):

Influenza Virus ◽

Virus Replication ◽

Drug Repositioning ◽

Antiviral Drug ◽

Influenza Viruses ◽

Influenza Virus Replication ◽

Approved Drugs ◽

Multiple Strains ◽

Tract Infections

Influenza viruses cause respiratory tract infections and substantial health concerns. Infection may result in mild to severe respiratory disease associated with morbidity and some mortality. Several anti-influenza drugs are available, but these agents target viral components and are susceptible to drug resistance. There is a need for new antiviral drug strategies that include repurposing of clinically approved drugs. Drugs that target cellular machinery necessary for influenza virus replication can provide a means for inhibiting influenza virus replication. We used RNA interference screening to identify key host cell genes required for influenza replication, and then FDA-approved drugs that could be repurposed for targeting host genes. We examined the effects of Clopidogrel and Triamterene to inhibit A/WSN/33 (EC50 5.84 uM and 31.48 uM, respectively), A/CA/04/09 (EC50 6.432 uM and 3.32 uM, respectively), and B/Yamagata/16/1988 (EC50 0.28 uM and 0.11 uM, respectively) replication. Clopidogrel and Triamterene provide a druggable approach to influenza treatment across multiple strains and subtypes.

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Identification of FDA Approved Drugs Targeting COVID-19 Virus by Structure-Based Drug Repositioning

10.26434/chemrxiv.12003930.v1 ◽

2020 ◽

Cited By ~ 3

Author(s):

Ayman Farag ◽

Ping Wang ◽

Mahmoud Ahmed ◽

Hesham Sadek

Keyword(s):

Drug Repositioning ◽

Binding Energies ◽

Binding Modes ◽

Structure Based Drug Design ◽

Protease Enzyme ◽

Starting Point ◽

Approved Drugs ◽

Fda Approved Drugs

<div>The new strain of Coronaviruses (SARS-CoV-2), and the resulting Covid-19 disease has spread swiftly across the globe after its initial detection in late December 2019 in Wuhan, China, resulting in a pandemic status declaration by WHO within 3 months. Given the heavy toll of this pandemic, researchers are actively testing various strategies including new and repurposed drugs as well as vaccines. In the current brief report, we adopted a repositioning approach using insilico molecular modeling screening using FDA approved drugs with established safety profiles for potential inhibitory effects on Covid-19 virus. We started with structure based drug design by screening more than 2000 FDA approved drugs</div><div>against Covid-19 virus main protease enzyme (Mpro) substrate-binding pocket to identify potential hits based on their binding energies, binding modes, interacting amino acids, and therapeutic indications. In addition, we elucidate preliminary pharmacophore features for candidates bound to Covid-19 virus Mpro substratebinding pocket. The top hits include anti-viral drugs such as Darunavir, Nelfinavirand Saquinavir, some of which are already being tested in Covid-19 patients. Interestingly, one of the most promising hits in our screen is the hypercholesterolemia drug Rosuvastatin. These results certainly do not confirm or indicate antiviral activity, but can rather be used as a starting point for further in vitro and in vivo testing, either individually or in combination.</div>

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Drug repositioning: A Unique Approach to Refurbish Drug Discovery

Current Drug Discovery Technologies ◽

10.2174/1570163818666210316114331 ◽

2021 ◽

Vol 18 ◽

Author(s):

Mayura A Kale ◽

Prashant B Shamkuwar ◽

Vishnukant K Mourya ◽

Aishwarya B Deshpande ◽

Priyanka A Shelke

Keyword(s):

Drug Discovery ◽

Drug Repositioning ◽

Cost Effective ◽

Positive Outcomes ◽

Computational Tools ◽

Therapeutic Implications ◽

Novel Drugs ◽

Unique Approach ◽

Approved Drugs

: Since a decade, it has been observed that there is remarkable decrease in the quantum of novel clinically approved drugsin spite of modernization in research and development process. We have highlighted repositioning of drugs as a methodology that has found new therapeutic implications for clinically approved drugs but with different indications. This can be considered as an upbringing strategy to deliver timely and cost-effective solutions which still needexplorationtoget over the shortage of number of novel drugs reaching market. This review focuses on activity-based drug repositioning approach, which is used to explore new uses of known drugs that are already approved for specific indications and are now being used for other indications on the basis ofthe fact that single drug interacts with multiple targets. It also includes current research trends related to drug repositioning which depends on strong knowledge of medicinal chemistry and involves elucidation of mechanisms of action and validation of novel targets. The review highlights theimportance totheusage of computational tools and databases of various forms for drug repositioning purposes which have enhanced the ability to pose reasonable and testable hypotheses. The critical nature of this aspect is obvious in cases where data gathered from in vitro or animal models do not confirm in subsequent clinical trials. Hence, considering positive outcomes of drug repositioning, it can be surmised that this approach can serve as promising one that can develop into a robust drug discovery strategy.

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FDA-Approved Drugs with Potent In Vitro Antiviral Activity against Severe Acute Respiratory Syndrome Coronavirus 2

Pharmaceuticals ◽

10.3390/ph13120443 ◽

2020 ◽

Vol 13 (12) ◽

pp. 443

Author(s):

Ahmed Mostafa ◽

Ahmed Kandeil ◽

Yaseen A. M. M. Elshaier ◽

Omnia Kutkat ◽

Yassmin Moatasim ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Antiviral Activity ◽

Drug Repositioning ◽

Data Bank ◽

Binding Mode ◽

Therapeutic Benefits ◽

Anti Inflammatory ◽

Approved Drugs ◽

Fda Approved Drugs

(1) Background: Drug repositioning is an unconventional drug discovery approach to explore new therapeutic benefits of existing drugs. Currently, it emerges as a rapid avenue to alleviate the COVID-19 pandemic disease. (2) Methods: Herein, we tested the antiviral activity of anti-microbial and anti-inflammatory Food and Drug Administration (FDA)-approved drugs, commonly prescribed to relieve respiratory symptoms, against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the viral causative agent of the COVID-19 pandemic. (3) Results: Of these FDA-approved antimicrobial drugs, Azithromycin, Niclosamide, and Nitazoxanide showed a promising ability to hinder the replication of a SARS-CoV-2 isolate, with IC50 of 0.32, 0.16, and 1.29 µM, respectively. We provided evidence that several antihistamine and anti-inflammatory drugs could partially reduce SARS-CoV-2 replication in vitro. Furthermore, this study showed that Azithromycin can selectively impair SARS-CoV-2 replication, but not the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). A virtual screening study illustrated that Azithromycin, Niclosamide, and Nitazoxanide bind to the main protease of SARS-CoV-2 (Protein data bank (PDB) ID: 6lu7) in binding mode similar to the reported co-crystalized ligand. Also, Niclosamide displayed hydrogen bond (HB) interaction with the key peptide moiety GLN: 493A of the spike glycoprotein active site. (4) Conclusions: The results suggest that Piroxicam should be prescribed in combination with Azithromycin for COVID-19 patients.

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Drug repurposing for ligand-induced rearrangement of Sirt2 active site-based inhibitors via molecular modeling and quantum mechanics calculations

Scientific Reports ◽

10.1038/s41598-021-89627-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shiv Bharadwaj ◽

Amit Dubey ◽

Nitin Kumar Kamboj ◽

Amaresh Kumar Sahoo ◽

Sang Gu Kang ◽

...

Keyword(s):

Simulation Analysis ◽

Drug Repurposing ◽

3D Qsar ◽

Computational Screening ◽

In Vitro Investigation ◽

Qsar Models ◽

Approved Drugs ◽

Dynamics Simulations ◽

Fda Approved Drugs

AbstractSirtuin 2 (Sirt2) nicotinamide adenine dinucleotide-dependent deacetylase enzyme has been reported to alter diverse biological functions in the cells and onset of diseases, including cancer, aging, and neurodegenerative diseases, which implicate the regulation of Sirt2 function as a potential drug target. Available Sirt2 inhibitors or modulators exhibit insufficient specificity and potency, and even partially contradictory Sirt2 effects were described for the available inhibitors. Herein, we applied computational screening and evaluation of FDA-approved drugs for highly selective modulation of Sirt2 activity via a unique inhibitory mechanism as reported earlier for SirReal2 inhibitor. Application of stringent molecular docking results in the identification of 48 FDA-approved drugs as selective putative inhibitors of Sirt2, but only top 10 drugs with docking scores > − 11 kcal/mol were considered in reference to SirReal2 inhibitor for computational analysis. The molecular dynamics simulations and post-simulation analysis of Sirt2-drug complexes revealed substantial stability for Fluphenazine and Nintedanib with Sirt2. Additionally, developed 3D-QSAR-models also support the inhibitory potential of drugs, which exclusively revealed highest activities for Nintedanib (pIC50 ≥ 5.90 µM). Conclusively, screened FDA-approved drugs were advocated as promising agents for Sirt2 inhibition and required in vitro investigation for Sirt2 targeted drug development.

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First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Inhibitors of Neuroblastoma Cell Colony Growth That Increase Lysosome Accumulation

10.26434/chemrxiv.12440096.v1 ◽

2020 ◽

Author(s):

Daniel Herp ◽

Johannes Ridinger ◽

Dina Robaa ◽

Stephen A. Shinsky ◽

Karin Schmidtkunz ◽

...

Keyword(s):

Histone Deacetylases ◽

High Throughput Screening ◽

Neuroblastoma Cell ◽

Hdac Inhibitors ◽

Anticancer Therapy ◽

Colony Growth ◽

Autophagic Flux ◽

Enzymatic Conversion ◽

Lysine Deacetylase

Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, esp. cancer. First HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement e.g. in the pathogenesis of neuroblastoma. This is due in part to a lack of robust enzymatic conversion assays. In contrast to the protein lysine deacetylase and deacylase activity of the other HDAC subtypes, it has recently been shown that HDAC10 has strong preferences for deacetylation of oligoamine substrates like spermine or spermidine. Hence, it also termed a polyamine deacetylase (PDAC). Here, we present the first fluorescent enzymatic conversion assay for HDAC10 using an aminocoumarin labelled acetyl spermidine derivative to measure its PDAC activity, which is suitable for high-throughput screening. Using this assay, we identified potent inhibitors of HDAC10 mediated spermidine deacetylation in-vitro. Among those are potent inhibitors of neuroblastoma colony growth in culture that show accumulation of lysosomes, implicating disturbance of autophagic flux.

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Repositioning Drugs for Rare Immune Diseases: Hopes and Challenges for a Precision Medicine

Current Medicinal Chemistry ◽

10.2174/0929867324666170830101215 ◽

2018 ◽

Vol 25 (24) ◽

pp. 2764-2782 ◽

Cited By ~ 3

Author(s):

Erica Valencic ◽

Alenka Smid ◽

Ziga Jakopin ◽

Alberto Tommasini ◽

Irena Mlinaric-Rascan

Keyword(s):

Precision Medicine ◽

Rare Diseases ◽

Business Models ◽

Drug Repositioning ◽

Drug Action ◽

Primary Immunodeficiency Diseases ◽

Computational Sciences ◽

Approved Drugs ◽

Molecular Mode ◽

Viable Business

Human primary immunodeficiency diseases (PIDs) are a large group of rare diseases and are characterized by a great genetic and phenotypic heterogeneity. A large subset of PIDs is genetically defined, which has a crucial impact for the understanding of the molecular basis of disease and the development of precision medicine. <p> Discovery and development of new therapies for rare diseases has long been de-privileged due to the length and cost of the processes involved. Interest has increased due to stimulatory regulatory and supportive reimbursement environments enabling viable business models. <p> Advancements in biomedical and computational sciences enable the development of rational, designed approaches for identification of novel indications of already approved drugs allowing faster delivery of new medicines. Drug repositioning is based either on clinical analogies of diseases or on understanding of the molecular mode of drug action and mechanisms of the disease. All of these are the basis for the development of precision medicine.

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