scholarly journals Repurposing of Antimicrobial Agents for Cancer Therapy: What Do We Know?

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3193
Author(s):  
Christina Pfab ◽  
Luisa Schnobrich ◽  
Samir Eldnasoury ◽  
André Gessner ◽  
Nahed El-Najjar
Keyword(s):  
Clinical Trials ◽  
Antimicrobial Agents ◽  
Large Body ◽  
Drug Repurposing ◽  
Extensive Discussion ◽  
Attrition Rates ◽  
Beneficial Effects ◽  
Stage Of Development ◽  
Development Costs ◽  
Approved Drugs

The substantial costs of clinical trials, the lengthy timelines of new drug discovery and development, along the high attrition rates underscore the need for alternative strategies for finding quickly suitable therapeutics agents. Given that most approved drugs possess more than one target tightly linked to other diseases, it encourages promptly testing these drugs in patients. Over the past decades, this has led to considerable attention for drug repurposing, which relies on identifying new uses for approved or investigational drugs outside the scope of the original medical indication. The known safety of approved drugs minimizes the possibility of failure for adverse toxicology, making them attractive de-risked compounds for new applications with potentially lower overall development costs and shorter development timelines. This latter case is an exciting opportunity, specifically in oncology, due to increased resistance towards the current therapies. Indeed, a large body of evidence shows that a wealth of non-cancer drugs has beneficial effects against cancer. Interestingly, 335 drugs are currently being evaluated in different clinical trials for their potential activities against various cancers (Redo database). This review aims to provide an extensive discussion about the anti-cancer activities exerted by antimicrobial agents and presents information about their mechanism(s) of action and stage of development/evaluation.

scholarly journals New Candidates for Furin Inhibition as Probable Treat for COVID-19: Docking Output

2021 ◽  
Author(s):  
Mohammad Reza Dayer
Keyword(s):  
Clinical Trials ◽  
Active Site ◽  
High Rate ◽  
Lower Side ◽  
Inhibitory Effects ◽  
Beneficial Effects ◽  
High Affinity ◽  
Constant Sequence ◽  
Site Characteristics ◽  
Approved Drugs

Abstract Furin is a serine protease that takes part in the processing and activation of the host cell pre-proteins. The enzyme also plays an important role in the activation of several viruses like the newly emerging SARS-CoV-2 virus that causes COVID-19 disease with a high rate of virulence and mortality. Unlike viral enzymes, furin owns a constant sequence and active site characteristics and seems to be a better target for drug design for COVID-19 treatment. Considering furin active site as receptor and some approved drugs from different classes including antiviral, antibiotics, and anti protozoa/anti parasites with suspected beneficial effects on COVID-19, as ligands we have carried out docking experiments in HEX software to pickup those capable to bind furin active site with high affinity and suggest them as probable candidates for clinical trials assessments. Our docking experiments show that saquinavir, nelfinavir, and atazanavir with cumulative inhibitory effects of 2.52, 2.16, and 2.13, respectively seem to be the best candidates for furin inhibition even in severe cases of COVID-19 as adjuvant therapy, while clarithromycin, niclosamide, and erythromycin with cumulative inhibitory indices of 1.97, 1.90, and 1.84, respectively with lower side effects than antiviral drugs could be suggested as prophylaxes for the first stage of COVID-19 treatment.

scholarly journals Automatic discovery of transferable patterns in protein-ligand interaction networks

2018 ◽  
Author(s):  
Aida Mrzic ◽  
Dries Van Rompaey ◽  
Stefan Naulaerts ◽  
Hans De Winter ◽  
Wim Vanden Berghe ◽  
...  
Keyword(s):  
Drug Target ◽  
Bacterial Resistance ◽  
Resistance Mechanisms ◽  
Frequent Itemset ◽  
Interaction Patterns ◽  
Ligand Interaction ◽  
Attrition Rates ◽  
Stage Of Development ◽  
Protein Ligand Interaction ◽  
Approved Drugs

In recent years, the pharmaceutical industry has been confronted with rising R&D costs paired with decreasing productivity. Attrition rates for new molecules are tremendous, with a substantial number of molecules failing in an advanced stage of development. Repositioning previously approved drugs for new indications can mitigate these issues by reducing both risk and cost of development. Computational methods have been developed to allow for the prediction of drug-target interactions, but it remains difficult to branch out into new areas of application where information is scarce. Here, we present a proof-of-concept for discovering patterns in protein-ligand data using frequent itemset mining. Two key advantages of our method are the transferability of our patterns to different application domains and the facile interpretation of our recommendations. Starting from a set of known protein-ligand relationships, we identify patterns of molecular substructures and protein domains that lie at the basis of these interactions. We show that these same patterns also underpin metabolic pathways in humans. We further demonstrate how association rules mined from human protein-ligand interaction patterns can be used to predict antibiotics susceptible to bacterial resistance mechanisms.

scholarly journals Identification of SARS-CoV-2–induced pathways reveals drug repurposing strategies

2021 ◽  
Vol 7 (27) ◽  
pp. eabh3032
Author(s):  
Namshik Han ◽  
Woochang Hwang ◽  
Konstantinos Tzelepis ◽  
Patrick Schmerer ◽  
Eliza Yankova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Viral Replication ◽  
Rapid Development ◽  
Drug Repurposing ◽  
Mechanisms Of Action ◽  
Neural Network Analysis ◽  
Cell Assays ◽  
Artificial Neural Network Analysis ◽  
Approved Drugs ◽  
Disease Signatures

The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates the rapid development of new therapies against coronavirus disease 2019 (COVID-19) infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2–induced protein network, based on disease signatures defined by COVID-19 multiomics datasets, and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2–induced pathways, 40 of which are already in COVID-19 clinical trials, testifying to the validity of the approach. Using artificial neural network analysis, we classified these 200 drugs into nine distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (126) and immune response (74). Two drugs (proguanil and sulfasalazine) implicated in viral replication were shown to inhibit replication in cell assays. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.

scholarly journals An Update on Antiviral Therapy Against SARS-CoV-2: How Far Have We Come?

2021 ◽  
Vol 12 ◽  
Author(s):  
Omkar Indari ◽  
Shweta Jakhmola ◽  
Elangovan Manivannan ◽  
Hem Chandra Jha
Keyword(s):  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Drug Repurposing ◽  
Clinical Findings ◽  
Open Label ◽  
Plasma Therapy ◽  
Clinical Safety ◽  
Treatment Research ◽  
Repurposed Drugs ◽  
Approved Drugs

COVID-19 pandemic has spread worldwide at an exponential rate affecting millions of people instantaneously. Currently, various drugs are under investigation to treat an enormously increasing number of COVID-19 patients. This dreadful situation clearly demands an efficient strategy to quickly identify drugs for the successful treatment of COVID-19. Hence, drug repurposing is an effective approach for the rapid discovery of frontline arsenals to fight against COVID-19. Successful application of this approach has resulted in the repurposing of some clinically approved drugs as potential anti-SARS-CoV-2 candidates. Several of these drugs are either antimalarials, antivirals, antibiotics or corticosteroids and they have been repurposed based on their potential to negate virus or reduce lung inflammation. Large numbers of clinical trials have been registered to evaluate the effectiveness and clinical safety of these drugs. Till date, a few clinical studies are complete and the results are primary. WHO also conducted an international, multi-country, open-label, randomized trials-a solidarity trial for four antiviral drugs. However, solidarity trials have few limitations like no placebos were used, additionally any drug may show effectiveness for a particular population in a region which may get neglected in solidarity trial analysis. The ongoing randomized clinical trials can provide reliable long-term follow-up results that will establish both clinical safety and clinical efficacy of these drugs with respect to different regions, populations and may aid up to worldwide COVID-19 treatment research. This review presents a comprehensive update on majorly repurposed drugs namely chloroquine, hydroxychloroquine, remdesivir, lopinavir-ritonavir, favipiravir, ribavirin, azithromycin, umifenovir, oseltamivir as well as convalescent plasma therapy used against SARS-CoV-2. The review also summarizes the data recorded on the mechanism of anti-SARS-CoV-2 activity of these repurposed drugs along with the preclinical and clinical findings, therapeutic regimens, pharmacokinetics, and drug-drug interactions.

scholarly journals In silico Drug Repurposing for COVID-19: Targeting SARS-CoV-2 Proteins through Docking and Quantum Mechanical Scoring

2020 ◽  
Author(s):  
Claudio Cavasotto ◽  
Juan Di Filippo
Keyword(s):  
Clinical Trials ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Rational Drug Design ◽  
World Health ◽  
Quantum Mechanical ◽  
S Protein ◽  
Compound Screening ◽  
Health Organization ◽  
Approved Drugs

In December 2019, an infectious disease caused by the coronavirus SARS-CoV-2 appeared in Wuhan, China. This disease (COVID-19) spread rapidly worldwide, and on March 2020 was declared a pandemic by the World Health Organization (WHO). Today, almost 1,5 million people have been infected, with more than 85,000 casualties. Today, no vaccine nor antiviral drug is available. While the development of a vaccine might take at least a year, and for a novel drug, even longer; finding a new use to an old drug (drug repurposing) could be the most effective strategy. We present a docking-based screening using a quantum mechanical scoring of a library built from approved drugs and compounds undergoing clinical trials, against three SARS-CoV-2 target proteins: the spike or S-protein, and two proteases, the main protease and the papain-like<br>protease. The S-protein binds directly to the Angiotensin Converting Enzyme 2 receptor of the human host cell surface, while the two proteases process viral polyproteins.<br>Following the anaylysis of our structure-based compound screening, we propose several structurally diverse compounds (either FDA-approved or in clinical trials) that could display antiviral activity against SARS-CoV-2. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against the disease. We hope that these findings may contribute to the rational drug design against COVID-19.

scholarly journals In silico Drug Repurposing for COVID-19: Targeting SARS-CoV-2 Proteins through Docking and Quantum Mechanical Scoring

2020 ◽  
Author(s):  
Claudio Cavasotto ◽  
Juan Di Filippo
Keyword(s):  
Clinical Trials ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Rational Drug Design ◽  
World Health ◽  
Quantum Mechanical ◽  
Chemical Library ◽  
S Protein ◽  
Health Organization ◽  
Approved Drugs

In December 2019, an infectious disease caused by the coronavirus SARS-CoV-2 appeared in Wuhan, China. This disease (COVID-19) spread rapidly worldwide, and on March 2020 was declared a pandemic by the World Health Organization (WHO). Today, more than 4.7 million people have been infected, with almost 320,000 casualties, while no vaccine nor antiviral drug is in sight. The development of a vaccine might take at least a year, and even longer for a novel drug; thus, finding a new use to an old drug (drug repurposing) could be the most effective strategy. We present a high-throughput docking approach using a novel quantum mechanical scoring for screening a chemical library of ~11,500 molecules built from FDA-approved drugs and compounds undergoing clinical trials, against three SARS-CoV-2 target proteins: the spike or S-protein, and two proteases, the main protease and the papain-like protease. The S-protein binds directly to the Angiotensin Converting Enzyme 2 receptor of the human host cell surface, while the two proteases process viral polyproteins. Following the analysis of our structure-based virtual screening, we propose several structurally diverse compounds that could display antiviral activity against SARS-CoV-2. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against the disease. We hope that these findings may contribute to the rational drug design against COVID-19.

scholarly journals Data-Driven Drug Repurposing for COVID-19

2020 ◽  
Author(s):  
Raghvendra Mall ◽  
Abdurrahman Elbasir ◽  
Hossam Al Meer ◽  
Sanjay Chawla ◽  
Ehsan Ullah
Keyword(s):  
Clinical Trials ◽  
De Novo ◽  
Drug Repurposing ◽  
Binding Energies ◽  
Protein Activity ◽  
De Novo Drug Design ◽  
Docking Simulations ◽  
Antibiotic Drugs ◽  
Approved Drugs ◽  
Ranked List

<div>Motivation: A global effort is underway to identify drugs for the treatment of COVID-19. Since de novo drug design is an extremely long, time-consuming, and expensive process, efforts are underway to discover existing drugs that can be</div><div>repurposed for COVID-19.</div><div><br></div><div>Model: We propose a machine learning representation framework that uses deep learning induced vector embeddings of drugs and viral proteins as features to predict drug-viral protein activity. The prediction model in-turn is used to build an ensemble framework to rank approved drugs based on their ability to inhibit the three main proteases (enzymes) of the SARS-COV-2 virus.</div><div><br></div><div>Results: We identify a ranked list of 19 drugs as potential targets including 7 antivirals, 6 anticancer, 3 antibiotics, 2 antimalarial, and 1 antifungal. Several drugs, such as Remdesivir, Lopinavir, Ritonavir, and Hydroxychloroquine, in our ranked list, are currently in clinical trials. Moreover, through molecular docking simulations, we demonstrate that majority of the anticancer and antibiotic drugs in our ranked list have low binding energies and thus high binding affinity with the 3CL-pro protease of SARS-COV-2 virus.</div><div><br></div><div>Disclaimer: Our models are computational and the drugs suggested should not be taken for treating COVID-19 without a doctor's advice, as further wet-lab research and clinical trials are essential to elucidate their efficacy for this purpose.</div>

Repositioning of drugs to counter COVID-19 pandemic - An Insight

2020 ◽  
Vol 21 ◽  
Author(s):  
Sai M. Akilesh ◽  
Rajesh J ◽  
Dhanabal Palanisamy ◽  
Ashish Wadhwani
Keyword(s):  
Clinical Trials ◽  
Drug Repurposing ◽  
Review Article ◽  
The Novel ◽  
Phylogenetic Relation ◽  
Scientific Investigations ◽  
Realistic Approach ◽  
Life Threatening ◽  
Novel Coronavirus ◽  
Approved Drugs

: COVID-19 is a coronavirus pandemic, caused by the novel coronavirus 2 (SARS-CoV-2) severe acute respiratory syndrome. The devastating impact of this novel coronavirus outbreak has necessitated the need for rapid and effective anti-viral therapies against SARS-CoV-2, to contain the spread of disease and importantly, alleviate the severe life-threatening symptoms and disorders. Drug repurposing strategy offers an attractive, immediate and realistic approach to tackle this growing pandemic of COVID-19. Due to the similarities with SARS-CoV-1 virus and phylogenetic relation to MERS-CoV virus, accelerated screening of approved drugs and development of repositioning strategies have proved to be critical in the survival of many COVID-19 patients. Numerous scientific investigations from the initial years of coronavirus outbreak along with upcoming advances of immunotherapy and vaccines may prove to be beneficial. Currently, several repurposing strategies are under different phases of clinical trials and provide with definitive framework for the development of future therapies for the effective treatment of COVID-19. This review article summarizes the latest developments and trends in drug repurposing strategy for COVID-19 treatment.

scholarly journals On the Generation of Novel Ligands for SARS-CoV-2 Protease and ACE2 Receptor via Constrained Graph Variational Autoencoders

2020 ◽  
Author(s):  
Jasper Kyle Catapang ◽  
Junie B. Billones
Keyword(s):  
Clinical Trials ◽  
Drug Discovery ◽  
Effective Treatment ◽  
Protease Inhibitors ◽  
Drug Repurposing ◽  
The Novel ◽  
Main Protease ◽  
Receptor Blockers ◽  
Approved Drugs ◽  
Novel Drug

SARS-CoV-2 has no known vaccine nor any effective treatment that has been released for clinical trials yet. This has ultimately paved the way for novel drug discovery approaches since although there are multiple efforts focused on drug repurposing of clinically-approved drugs for SARS-CoV-2, it is also worth considering that these existing drugs can be surpassed in effectivity by novel ones. This research focuses on the generation of novel candidate inhibitors via constrained graph variational autoencoders and the calculation of their Tanimoto similarities against existing drugs---repurposing these existing drugs and considering the novel ligands as possible SARS-CoV-2 main protease inhibitors and ACE2 receptor blockers by docking them through PyRx and ranking these ligands.

scholarly journals In silico Drug Repurposing for COVID-19: Targeting SARS-CoV-2 Proteins through Docking and Quantum Mechanical Scoring

2020 ◽  
Author(s):  
Claudio Cavasotto ◽  
Juan Di Filippo
Keyword(s):  
Clinical Trials ◽  
Antiviral Drug ◽  
Drug Repurposing ◽  
Rational Drug Design ◽  
World Health ◽  
Quantum Mechanical ◽  
Chemical Library ◽  
S Protein ◽  
Health Organization ◽  
Approved Drugs

In December 2019, an infectious disease caused by the coronavirus SARS-CoV-2 appeared in Wuhan, China. This disease (COVID-19) spread rapidly worldwide, and on March 2020 was declared a pandemic by the World Health Organization (WHO). Today, more than 4.7 million people have been infected, with almost 320,000 casualties, while no vaccine nor antiviral drug is in sight. The development of a vaccine might take at least a year, and even longer for a novel drug; thus, finding a new use to an old drug (drug repurposing) could be the most effective strategy. We present a high-throughput docking approach using a novel quantum mechanical scoring for screening a chemical library of ~11,500 molecules built from FDA-approved drugs and compounds undergoing clinical trials, against three SARS-CoV-2 target proteins: the spike or S-protein, and two proteases, the main protease and the papain-like protease. The S-protein binds directly to the Angiotensin Converting Enzyme 2 receptor of the human host cell surface, while the two proteases process viral polyproteins. Following the analysis of our structure-based virtual screening, we propose several structurally diverse compounds that could display antiviral activity against SARS-CoV-2. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against the disease. We hope that these findings may contribute to the rational drug design against COVID-19.

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