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Alternative Therapies in Health and... Aug 2020Drug repurposing is a relevant approach during the COVID-19 pandemic, because development of new drugs is time-consuming and costly, and the safety of new drugs is... (Review)
Review
CONTEXT
Drug repurposing is a relevant approach during the COVID-19 pandemic, because development of new drugs is time-consuming and costly, and the safety of new drugs is paramount. Drug repurposing focuses on researching new indications for existing drugs and can reduce the challenges faced in drug development.
OBJECTIVE
The current review intended to examine the current status of drugs being repurposed for COVID-19 treatment.
DESIGN
The research team performed a literature review, searching relevant literature databases to find abstracts of relevant articles in journals published from 2010 until May 16, 2020. The sources of data included Google Scholar, PubMed, and ScienceDirect. The search terms used included repositioning of drugs, repurposing of drugs and COVID-19 therapy, and SARS-CoV-2 therapy.
SETTING
The research team conducted this study at the Department of Pharmacology, Punjab University College of Pharmacy, University of the Punjab, Lahore, Pakistan; Mangalbare Hospital, Morang, Nepal; and Dr Iwamura Memorial Hospital, Bhaktapur, Nepal.
RESULTS
Repurposing of drugs from different pharmacological groups including antivirals like remdesivir, lopinavir, ritonavir, arbidol, oseltamivir, penciclovir, favipiravir, ganciclovir, and ribavirin; other antibiotics like azithromycin, ivermectin, eravacycline, valrubicin, streptomycin, nitazoxanide, teicoplanin, caspofungin, and colistin; and other agents like hydroxychloroquine, chloroquine, tocilizumab, camostat, nafamostat, carfilzomib, interferon, aprepitant, and dexamethasone can be considered for COVID-19 therapy.
CONCLUSIONS
Although current results are promising, limitations to drug repurposing, such as a low success rate and the possibility of adverse events, can't be overlooked. With continuous research and technical advancements, repurposing will no doubt provide a notable scientific contribution to innovation in drug development and pharmacotherapy practice for the treatment of new diseases or existing diseases in a new way.
Topics: Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus Infections; Drug Repositioning; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 32827400
DOI: No ID Found -
Current Topics in Medicinal Chemistry 2020The vast geographical expansion of novel coronavirus and an increasing number of COVID-19 affected cases have overwhelmed health and public health services. Artificial...
BACKGROUND
The vast geographical expansion of novel coronavirus and an increasing number of COVID-19 affected cases have overwhelmed health and public health services. Artificial Intelligence (AI) and Machine Learning (ML) algorithms have extended their major role in tracking disease patterns, and in identifying possible treatments.
OBJECTIVE
This study aims to identify potential COVID-19 protease inhibitors through shape-based Machine Learning assisted by Molecular Docking and Molecular Dynamics simulations.
METHODS
31 Repurposed compounds have been selected targeting the main coronavirus protease (6LU7) and a machine learning approach was employed to generate shape-based molecules starting from the 3D shape to the pharmacophoric features of their seed compound. Ligand-Receptor Docking was performed with Optimized Potential for Liquid Simulations (OPLS) algorithms to identify highaffinity compounds from the list of selected candidates for 6LU7, which were subjected to Molecular Dynamic Simulations followed by ADMET studies and other analyses.
RESULTS
Shape-based Machine learning reported remdesivir, valrubicin, aprepitant, and fulvestrant as the best therapeutic agents with the highest affinity for the target protein. Among the best shape-based compounds, a novel compound identified was not indexed in any chemical databases (PubChem, Zinc, or ChEMBL). Hence, the novel compound was named 'nCorv-EMBS'. Further, toxicity analysis showed nCorv-EMBS to be suitable for further consideration as the main protease inhibitor in COVID-19.
CONCLUSION
Effective ACE-II, GAK, AAK1, and protease 3C blockers can serve as a novel therapeutic approach to block the binding and attachment of the main COVID-19 protease (PDB ID: 6LU7) to the host cell and thus inhibit the infection at AT2 receptors in the lung. The novel compound nCorv- EMBS herein proposed stands as a promising inhibitor to be evaluated further for COVID-19 treatment.
Topics: Algorithms; Betacoronavirus; COVID-19; Coronavirus Infections; Data Mining; Databases, Factual; Drug Repositioning; Humans; Ligands; Machine Learning; Models, Theoretical; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Structure; Pandemics; Pneumonia, Viral; Protease Inhibitors; SARS-CoV-2
PubMed: 32621718
DOI: 10.2174/1568026620666200704135327 -
ChemRxiv : the Preprint Server For... Feb 2020The recent outbreak of novel coronavirus disease -19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to...
The recent outbreak of novel coronavirus disease -19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D-structures of key virous proteins are resolved. Taking the advantage of a recently released crystal structure of COVID-19 protease in complex with a covalently-bonded inhibitor, N3, I conducted virtual docking screening of approved drugs and drug candidates in clinical trials. For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an endpoint method called MM-PBSA-WSAS. Several promising known drugs stand out as potential inhibitors of COVID-19 protease, including Carfilzomib, Eravacycline, Valrubicin, Lopinavir and Elbasvir. Carfilzomib, an approved anti-cancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, -13.82 kcal/mol. Streptomycin, an antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3.82 kcal/mol) is not nearly as low as that of the neutral form (-7.92 kcal/mol). One bioactive, PubChem 23727975, has a binding free energy of -12.86 kcal/mol. Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified. I found that one hotspot residue HIS41, is a conserved residue across many viruses including COVID-19, SARS, MERS, and HCV. The findings of this study can facilitate rational drug design targeting the COVID-19 protease.
PubMed: 32510523
DOI: 10.26434/chemrxiv.11875446 -
Journal of Chemical Information and... Jun 2020The recent outbreak of novel coronavirus disease-19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to...
The recent outbreak of novel coronavirus disease-19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D structures of key viral proteins are resolved. The virus causing COVID-19 is SARS-CoV-2. Taking advantage of a recently released crystal structure of SARS-CoV-2 main protease in complex with a covalently bonded inhibitor, N3 (Liu et al., 10.2210/pdb6LU7/pdb), I conducted virtual docking screening of approved drugs and drug candidates in clinical trials. For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an end point method called MM-PBSA-WSAS (molecular mechanics/Poisson-Boltzmann surface area/weighted solvent-accessible surface area; Wang, 2019, 119, 9478; Wang, 2006, 2, 287; Wang; ; Hou , 2012, 52, 1199). Several promising known drugs stand out as potential inhibitors of SARS-CoV-2 main protease, including carfilzomib, eravacycline, valrubicin, lopinavir, and elbasvir. Carfilzomib, an approved anticancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, -13.8 kcal/mol. The second-best repurposing drug candidate, eravacycline, is synthetic halogenated tetracycline class antibiotic. Streptomycin, another antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3.8 kcal/mol) is not nearly as low as that of the neutral form (-7.9 kcal/mol). One bioactive, PubChem 23727975, has a binding free energy of -12.9 kcal/mol. Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified. I found that one hot spot residue, His41, is a conserved residue across many viruses including SARS-CoV, SARS-CoV-2, MERS-CoV, and hepatitis C virus (HCV). The findings of this study can facilitate rational drug design targeting the SARS-CoV-2 main protease.
Topics: Anti-Bacterial Agents; Betacoronavirus; COVID-19; Coronavirus 3C Proteases; Coronavirus Infections; Cysteine Endopeptidases; Drug Repositioning; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Oligopeptides; Pandemics; Pneumonia, Viral; Protease Inhibitors; SARS-CoV-2; Tetracyclines; Thermodynamics; Time Factors; Viral Nonstructural Proteins
PubMed: 32315171
DOI: 10.1021/acs.jcim.0c00179 -
PloS One 2019Anthracyclines are a class of pharmaceuticals used in cancer treatment have the potential to negatively impact the environment. To study the possibilities of... (Comparative Study)
Comparative Study
Anthracyclines are a class of pharmaceuticals used in cancer treatment have the potential to negatively impact the environment. To study the possibilities of anthracyclines (represented by pirarubicin and valrubicin) removal, chemical inactivation using NaOH (0.01 M) and NaClO (5%) as decontamination agents and adsorption to powdered nanocrystalline titanium dioxide (TiO2) were compared. The titanium dioxide (TiO2) nanoparticles were prepared via homogeneous precipitation of an aqueous solution of titanium (IV) oxy-sulfate (TiOSO4) at different amount (5-120 g) with urea. The as-prepared TiO2 samples were characterized by XRD, HRSEM and nitrogen physisorption. The adsorption process of anthracycline cytostatics was determined followed by high-performance liquid chromatography coupled with mass spectrometry (LC-MS) and an in-situ Diffuse Reflectance Infrared Fourier Transform Spectroscopy (DRIFTS) technique. It was found that NaClO decomposes anthracyclines to form various transformation products (TPs). No TPs were identified after the reaction of valrubicin with a NaOH solution as well as in the presence of TiO2 nanoparticles. The best degree of removal, 100% of pirarubicin and 85% of valrubicin, has been achieved in a sample with 120 grams of TiOSO4 (TIT120) and TiO2 with 60 grams (TIT60), respectively.
Topics: Adsorption; Crystallization; Cytostatic Agents; Decontamination; Doxorubicin; Hydrolysis; Nanostructures; Particle Size; Sodium Hydroxide; Sodium Hypochlorite; Surface Properties; Titanium; Water Pollutants, Chemical
PubMed: 31603899
DOI: 10.1371/journal.pone.0223117 -
Expert Opinion on Investigational Drugs Sep 2019: The current first line therapy for high grade (HG) non-muscle invasive bladder cancer (NMIBC) is intravesical Bacillus Calmette-Guerin (BCG). Patients who recur or... (Review)
Review
: The current first line therapy for high grade (HG) non-muscle invasive bladder cancer (NMIBC) is intravesical Bacillus Calmette-Guerin (BCG). Patients who recur or progress despite BCG are recommended to undergo radical cystectomy or participate in clinical trials. There is an urgent need for alternative therapies in the BCG-unresponsive NMIBC realm. : We queried clinicaltrials.gov and pubmed.gov for current and recently completed early clinical trials pertaining to investigational agents used for the treatment of BCG-unresponsive NMIBC. These included intravesical chemotherapy, immunotherapy, vaccines, gene therapy, viruses, and agents used with novel drug delivery methods. In this article, we discuss the treatment guidelines for non-muscle invasive bladder cancer and therapeutic approaches under investigation in clinical trials. : The FDA is currently allowing single-arm studies as a pathway for approval in BCG-refractory patients with CIS. Although many agents are currently undergoing testing, none have been approved since Valrubicin. Hopefully, we will identify therapies sufficiently effective and durable to achieve FDA approval. Other considerations in this realm include the use of biomarkers in NMIBC to identify patients who will most likely respond to specific interventions. In addition, as systemic agents such as checkpoint inhibitors, are studied further, a multidisciplinary approach may be needed to treat this subset of patients.
Topics: Animals; Antineoplastic Agents; BCG Vaccine; Biomarkers, Tumor; Cystectomy; Drug Delivery Systems; Drugs, Investigational; Humans; Immunotherapy; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms
PubMed: 31412742
DOI: 10.1080/13543784.2019.1655730 -
Current Opinion in Urology May 2019To give an overview of current options for conservative treatment of patients failing intravesical bacillus Calmette-Guerin (BCG) and to discuss emerging approaches with...
PURPOSE OF REVIEW
To give an overview of current options for conservative treatment of patients failing intravesical bacillus Calmette-Guerin (BCG) and to discuss emerging approaches with potential future clinical applications.
RECENT FINDINGS
Radical cystectomy is the standard-of-care for patients failing BCG therapy. In patients unfit or unwilling to undergo surgery, salvage therapy options could be proposed with the aim to offer local cancer control and prevent progression to muscle-invasive disease. Salvage treatments have been conducted using intravesical chemotherapy regimens, chemoradiation or chemohyperthermia. Intravesical agents such as valrubicin, gemcitabine or docetaxel showed response rates varying between 16 and 40%, whereas combination treatments of gemcitabine with docetaxel or mitomycin reported response rates in up to 50% of all patients with durable responses in about one out of three patients. For chemohyperthermia, 2-year recurrence rates between 41 and 56% have been reported. Ongoing clinical trials are evaluating chemoradiation as well as novel approaches such as systemic immunotherapy, viral gene therapy, targeted therapy or vaccination strategies with promising preliminary outcomes.
SUMMARY
Salvage therapeutic bladder-sparing strategies for BCG failure such as intravesical chemotherapy or chemoradiation should currently only be considered in patients unfit for or refusing surgery. Innovative concepts such as chemohyperthermia, checkpoint inhibitors, targeted therapy or viral gene therapy could lead to major changes in clinical management of BCG failures in the future.
Topics: Adjuvants, Immunologic; Administration, Intravesical; BCG Vaccine; Cystectomy; Humans; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Salvage Therapy; Treatment Failure; Urinary Bladder Neoplasms
PubMed: 30762670
DOI: 10.1097/MOU.0000000000000593 -
World Journal of Urology Oct 2019BCG is the gold standard in management of high-risk non-muscle invasive bladder cancer (HRNMIBC). However, in patients who fail BCG, there are few effective... (Review)
Review
PURPOSE
BCG is the gold standard in management of high-risk non-muscle invasive bladder cancer (HRNMIBC). However, in patients who fail BCG, there are few effective intrasvesical options. This review aims to explore standard and emerging therapies in HRNMIBC.
METHODS
A non-systematic literature review was performed using Medline and PubMed. Literature focused on HRNMIBC and BCG failure studies, with particular attention to Phase II and III clinical trials.
RESULTS
The only FDA approved therapy for BCG failure patients in Valrubicin. Patients with HRNMIBC and BCG failure patients are at increased risk for progression and death from bladder cancer. There are a variety of clinical trials exploring different therapeutic approaches such as immunotherapy, vaccines, radiotherapy, and gene therapy. These trials are showing some promise in the early reporting phase.
CONCLUSION
Despite limited intravesical treatment options in BCG failure patients, there are several promising therapies currently being developed and several with promising early results.
Topics: Adjuvants, Immunologic; Antineoplastic Agents; BCG Vaccine; Humans; Neoplasm Invasiveness; Risk Assessment; Urinary Bladder Neoplasms
PubMed: 30515595
DOI: 10.1007/s00345-018-2592-0 -
Treatment Options for Patients with Recurrent Tumors After BCG Therapy: Are We Ignoring the Obvious?European Urology Oct 2018Treatment options are limited for non-muscle-invasive bladder cancer patients having failed BCG treatment who cannot undergo cystectomy. While results from ongoing...
Treatment options are limited for non-muscle-invasive bladder cancer patients having failed BCG treatment who cannot undergo cystectomy. While results from ongoing clinical trials are awaited, data have emerged suggesting that combination of agents having previously demonstrated safety and efficacy in this setting can help a large percentage of our patients. These data should not be ignored.
Topics: Adjuvants, Immunologic; Antineoplastic Agents; BCG Vaccine; Carcinoma, Transitional Cell; Clinical Trials as Topic; Cystectomy; Doxorubicin; Humans; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasm Staging; Patient Selection; Practice Guidelines as Topic; Urinary Bladder Neoplasms
PubMed: 29685644
DOI: 10.1016/j.eururo.2018.04.012 -
Journal of Pharmaceutical Analysis Jun 2017In this study, the molecular interactions between valrubicin, an anticancer drug, and fish sperm DNA have been studied in phosphate buffer solution (pH 7.4) using UV-Vis...
In this study, the molecular interactions between valrubicin, an anticancer drug, and fish sperm DNA have been studied in phosphate buffer solution (pH 7.4) using UV-Vis spectrophotometry and cyclic voltammetry techniques. Valrubicin intercalated into double stranded DNA under a weak displacement reaction with methylene blue (MB) molecule in a competitive reaction. The binding constant () of valrubicin-DNA was determined as 1.75×10 L/mol by spectrophotometric titration. The value of non-electrostatic binding constant ([Formula: see text]) was almost constant at different ionic strengths while the ratio of [Formula: see text]/ increased from 4.51% to 23.77%. These results indicate that valrubicin binds to ds-DNA via electrostatic and intercalation modes. Thermodynamic parameters including ΔH, ΔS and ΔG for valrubicin-DNA interaction were determined as -25.21×10 kJ/mol, 1.55×10 kJ/mol K and -22.03 kJ/mol, respectively. Cyclic voltammetry study shows a pair of redox peaks for valrubicin at 0.45 V and 0.36 V (vs. Ag/AgCl). The peak currents decreased and peak positions shifted to positive direction in the presence of DNA, showing intercalation mechanism due to the variation in formal potential.
PubMed: 29404035
DOI: 10.1016/j.jpha.2017.01.003