Two Possible Strategies for Drug Modification of Gemcitabine and Future Contributions to Personalized Medicine

Drug repurposing is an emerging strategy, which uses already approved drugs for new medical indications. One such drug is gemcitabine, an anticancer drug that only works at high doses since a portion is deactivated in the serum, which causes toxicity. In this review, two methods were discussed that could improve the anticancer effect of gemcitabine. The first is a chemical modification by conjugation with cell-penetrating peptides, namely penetratin, pVEC, and different kinds of CPP6, which mostly all showed an increased anticancer effect. The other method is combining gemcitabine with repurposed drugs, namely itraconazole, which also showed great cancer cell inhibition growth. Besides these two strategies, physiologically based pharmacokinetic models (PBPK models) are also the key for predicting drug distribution based on physiological data, which is very important for personalized medicine, so that the correct drug and dosage regimen can be administered according to each patient’s physiology. Taking all of this into consideration, it is believed that gemcitabine can be repurposed to have better anticancer effects.

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Structural Basis of Antisickling Effects of Selected FDA Approved Drugs: A Drug Repurposing Study

Current Computer - Aided Drug Design ◽

10.2174/1573409914666180129163711 ◽

2018 ◽

Vol 14 (2) ◽

pp. 106-116 ◽

Cited By ~ 1

Author(s):

Olujide O. Olubiyi ◽

Maryam O. Olagunju ◽

James O. Oni ◽

Abidemi O. Olubiyi

Keyword(s):

Drug Repurposing ◽

Structural Basis ◽

Approved Drugs ◽

Fda Approved Drugs

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Screening of an FDA-Approved Library for Novel Drugs against Y. pestis

Antibiotics ◽

10.3390/antibiotics10010040 ◽

2021 ◽

Vol 10 (1) ◽

pp. 40

Author(s):

David Gur ◽

Theodor Chitlaru ◽

Emanuelle Mamroud ◽

Ayelet Zauberman

Keyword(s):

Drug Repurposing ◽

Mortality Rates ◽

Systematic Screening ◽

Antibiotic Resistant ◽

Gram Negative ◽

Therapy Initiation ◽

Novel Drugs ◽

Resistant Strains ◽

Approved Drugs ◽

Fda Approved Drugs

Yersinia pestis is a Gram-negative pathogen that causes plague, a devastating disease that kills millions worldwide. Although plague is efficiently treatable by recommended antibiotics, the time of antibiotic therapy initiation is critical, as high mortality rates have been observed if treatment is delayed for longer than 24 h after symptom onset. To overcome the emergence of antibiotic resistant strains, we attempted a systematic screening of Food and Drug Administration (FDA)-approved drugs to identify alternative compounds which may possess antibacterial activity against Y. pestis. Here, we describe a drug-repurposing approach, which led to the identification of two antibiotic-like activities of the anticancer drugs bleomycin sulfate and streptozocin that have the potential for designing novel antiplague therapy approaches. The inhibitory characteristics of these two drugs were further addressed as well as their efficiency in affecting the growth of Y. pestis strains resistant to doxycycline and ciprofloxacin, antibiotics recommended for plague treatment.

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

Cancers ◽

10.3390/cancers13133193 ◽

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.

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In Silico Modeling of FDA-Approved Drugs for Discovery of Therapies Against Neglected Diseases: A Drug Repurposing Approach

In Silico Drug Design ◽

10.1016/b978-0-12-816125-8.00021-3 ◽

2019 ◽

pp. 625-648 ◽

Cited By ~ 2

Author(s):

Carolina L. Belllera ◽

María L. Sbaraglini ◽

Lucas N. Alberca ◽

Juan I. Alice ◽

Alan Talevi

Keyword(s):

In Silico ◽

Drug Repurposing ◽

Neglected Diseases ◽

In Silico Modeling ◽

Approved Drugs ◽

Fda Approved Drugs

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Potential 2019-nCoV 3C-like Protease Inhibitors Designed Using Generative Deep Learning Approaches

10.26434/chemrxiv.11829102.v1 ◽

2020 ◽

Cited By ~ 7

Author(s):

Alex Zhavoronkov ◽

Vladimir Aladinskiy ◽

Alexander Zhebrak ◽

Bogdan Zagribelnyy ◽

Victor Terentiev ◽

...

Keyword(s):

Homology Modelling ◽

Drug Repurposing ◽

Hiv Protease ◽

Learning Approaches ◽

Protein Targets ◽

Chemical Libraries ◽

Internal Resources ◽

Novel Coronavirus ◽

Approved Drugs ◽

Novel Drug

<div> <div> <div> <p>The emergence of the 2019 novel coronavirus (2019-nCoV), for which there is no vaccine or any known effective treatment created a sense of urgency for novel drug discovery approaches. One of the most important 2019-nCoV protein targets is the 3C-like protease for which the crystal structure is known. Most of the immediate efforts are focused on drug repurposing of known clinically-approved drugs and virtual screening for the molecules available from chemical libraries that may not work well. For example, the IC50 of lopinavir, an HIV protease inhibitor, against the 3C-like protease is approximately 50 micromolar. In an attempt to address this challenge, on January 28th, 2020 Insilico Medicine decided to utilize a part of its generative chemistry pipeline to design novel drug-like inhibitors of 2019-nCoV and started generation on January 30th. It utilized three of its previously validated generative chemistry approaches: crystal-derived pocked- based generator, homology modelling-based generation, and ligand-based generation. Novel druglike compounds generated using these approaches are being published at www.insilico.com/ncov-sprint/ and will be continuously updated. Several molecules will be synthesized and tested using the internal resources; however, the team is seeking collaborations to synthesize, test, and, if needed, optimize the published molecules. </p> </div> </div> </div>

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Deciphering the interactions of SARS-CoV-2 proteins with human ion channels using machine learning-based method

10.21203/rs.3.rs-622770/v1 ◽

2021 ◽

Author(s):

Nupur S. Munjal ◽

Dikscha Sapra ◽

Abhishek Goyal ◽

K.T. Shreya Parthasarathi ◽

Akhilesh Pandey ◽

...

Keyword(s):

Machine Learning ◽

Ion Channels ◽

Protein Interactions ◽

Transient Receptor Potential ◽

Trp Channels ◽

Transmission Rate ◽

Drug Repurposing ◽

Receptor Potential ◽

Ppi Networks ◽

Approved Drugs

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the worldwide COVID-19 pandemic which began in 2019. It has a high transmission rate and pathogenicity leading to health emergencies and economic crisis. Recent studies pertaining to the understanding of the molecular pathogenesis of SARS-CoV-2 infection exhibited the indispensable role of ion channels in viral infection inside the host. Moreover, machine learning-based algorithms are providing higher accuracy for host-SARS-CoV-2 protein-protein interactions (PPIs). In this study, predictions of PPIs of SARS-CoV-2 proteins with human ion channels (HICs) were performed using PPI-MetaGO algorithm. The PPIs were predicted with 82.71% accuracy, 84.09% precision, 84.09% sensitivity, 0.89 AUC-ROC, 65.17% MCC score and 84.09% F1 score. Thereafter, PPI networks of SARS-CoV-2 proteins with HICs were generated. Furthermore, biological pathway analysis of HICs interacting with SARS-CoV-2 proteins showed the involvement of six pathways, namely inflammatory mediator regulation of TRP channels, insulin secretion, renin secretion, gap junction, taste transduction and apelin signaling pathway. The inositol 1,4,5-trisphosphate receptor 1 (ITPR1) and transient receptor potential cation channel subfamily A member 1 (TRPA1) were identified as potential target proteins. Various FDA approved drugs interacting with ITPR1 and TRPA1 are also available. It is anticipated that targeting ITPR1 and TRPA1 may provide a better therapeutic management of infection caused by SARS-CoV-2. The study also reinforces the drug repurposing approach for the development of host directed antiviral drugs.

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Off-Label Medication: From a Simple Concept to Complex Practical Aspects

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph181910447 ◽

2021 ◽

Vol 18 (19) ◽

pp. 10447

Author(s):

Carmen-Maria Rusz ◽

Bianca-Eugenia Ősz ◽

George Jîtcă ◽

Amalia Miklos ◽

Mădălina-Georgiana Bătrînu ◽

...

Keyword(s):

Rare Diseases ◽

Drug Repurposing ◽

Regulatory Agencies ◽

Systematic Research ◽

Clinical Practices ◽

Safe Practice ◽

Safety Issues ◽

Off Label ◽

Simple Concept ◽

Approved Drugs

Off-label use of drugs is widely known as unapproved use of approved drugs, and it can be perceived as a relatively simple concept. Even though it has been in existence for many years, prescribing and dispensing of drugs in an off-label regimen is still a current issue, triggered especially by unmet clinical needs. Several therapeutic areas require off-label approaches; therefore, this practice is challenging for prescribing physicians. Meanwhile, the regulatory agencies are making efforts in order to ensure a safe practice. The present paper defines the off-label concept, and it describes its regulation, together with several complex aspects associated with clinical practices regarding rare diseases, oncology, pediatrics, psychiatry therapeutic areas, and the safety issues that arise. A systematic research of the literature was performed, using terms, such as “off-label”, ”prevalence”, ”rare diseases”, ”oncology”, ”psychiatry”, ”pediatrics”, and ”drug repurposing”. There are several reasons for which off-label practice remains indispensable in the present; therefore, efforts are made worldwide, by the regulatory agencies and governmental bodies, to raise awareness and to ensure safe practice, while also encouraging further research.

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