scholarly journals Tackling the Behavior of Cancer Cells: Molecular Bases for Repurposing Antipsychotic Drugs in the Treatment of Glioblastoma

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 263
Author(s):  
Michele Persico ◽  
Claudia Abbruzzese ◽  
Silvia Matteoni ◽  
Paola Matarrese ◽  
Anna Maria Campana ◽  
...  
Keyword(s):  
Antipsychotic Drugs ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Cancer Therapeutics ◽  
Research Process ◽  
New Drugs ◽  
Hallmarks Of Cancer ◽  
Dismal Prognosis ◽  
Wide Range ◽  
Molecular Bases

Glioblastoma (GBM) is associated with a very dismal prognosis, and current therapeutic options still retain an overall unsatisfactorily efficacy in clinical practice. Therefore, novel therapeutic approaches and effective medications are highly needed. Since the development of new drugs is an extremely long, complex and expensive process, researchers and clinicians are increasingly considering drug repositioning/repurposing as a valid alternative to the standard research process. Drug repurposing is also under active investigation in GBM therapy, since a wide range of noncancer and cancer therapeutics have been proposed or investigated in clinical trials. Among these, a remarkable role is played by the antipsychotic drugs, thanks to some still partially unexplored, interesting features of these agents. Indeed, antipsychotic drugs have been described to interfere at variable incisiveness with most hallmarks of cancer. In this review, we analyze the effects of antipsychotics in oncology and how these drugs can interfere with the hallmarks of cancer in GBM. Overall, according to available evidence, mostly at the preclinical level, it is possible to speculate that repurposing of antipsychotics in GBM therapy might contribute to providing potentially effective and inexpensive therapies for patients with this disease.

Recent Advances in Drug Repurposing for Parkinson’s Disease

2019 ◽  
Vol 26 (28) ◽  
pp. 5340-5362 ◽  
Author(s):  
Xin Chen ◽  
Giuseppe Gumina ◽  
Kristopher G. Virga
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Discovery ◽  
De Novo ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Cost Effective ◽  
New Drugs ◽  
Recent Advances ◽  
Clinical Drugs

:As a long-term degenerative disorder of the central nervous system that mostly affects older people, Parkinson’s disease is a growing health threat to our ever-aging population. Despite remarkable advances in our understanding of this disease, all therapeutics currently available only act to improve symptoms but cannot stop the disease progression. Therefore, it is essential that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson’s disease. Drug repurposing, also known as drug repositioning, or the process of finding new uses for existing or abandoned pharmaceuticals, has been recognized as a cost-effective and timeefficient way to develop new drugs, being equally promising as de novo drug discovery in the field of neurodegeneration and, more specifically for Parkinson’s disease. The availability of several established libraries of clinical drugs and fast evolvement in disease biology, genomics and bioinformatics has stimulated the momentums of both in silico and activity-based drug repurposing. With the successful clinical introduction of several repurposed drugs for Parkinson’s disease, drug repurposing has now become a robust alternative approach to the discovery and development of novel drugs for this disease. In this review, recent advances in drug repurposing for Parkinson’s disease will be discussed.

scholarly journals Drug Repurposing: A Review

2021 ◽  
pp. 161-169
Author(s):  
Rani Teksinh Bhagat ◽  
Santosh Ramarao Butle
Keyword(s):  
Drug Development ◽  
Research And Development ◽  
Development Process ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
New Drugs ◽  
Preclinical Development ◽  
Therapeutic Uses ◽  
Original Application ◽  
Approved Drugs

The drug development is a very time consuming and complex process. Drug development Process is Expensive. Success rate for the new drug development is very small. In recent years, decreases the new drugs development. The powerful tools are developed to support the research and development (R&D) process is essential. The Drug repurposing are helpful for research and development process. The drug re-purposing as an approach finds new therapeutic uses for current candidates or existing candidates or approved drugs, different from its original application. The main aimed of Drug repurposing is to reduce costs and research time investments in Research & Development. It is used for the diagnosis and treatment of various diseases. Repositioning is important over traditional approaches and need for effective therapies. Drug re-purposing identifies new application for already banned or existing drugs from market. In drug design, drug repurposing plays important role, because it helps to preclinical development. It reducing time efforts, expenses and failures in drug discovery process. It is also called as drug repositioning, drug redirecting, drug reprofiling.

Repurposing of Copper(II)-chelating Drugs for the Treatment of Neurodegenerative Diseases

2018 ◽  
Vol 25 (4) ◽  
pp. 525-539 ◽  
Author(s):  
Valeria Lanza ◽  
Danilo Milardi ◽  
Giuseppe Di Natale ◽  
Giuseppe Pappalardo
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
New Drugs ◽  
Toxicity Tests ◽  
Clinical Aspects ◽  
Drug Candidates ◽  
Metal Chelating ◽  
Neuronal Functions

Background: There is mounting urgency to find new drugs for the treatment of neurodegenerative disorders. A large number of reviews have exhaustively described either the molecular or clinical aspects of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). Conversely, reports outlining how known drugs in use for other diseases can also be effective as therapeutic agents in neurodegenerative diseases are less reported. This review focuses on the current uses of some copper(II) chelating molecules as potential drug candidates in neurodegeneration. Methods: Starting from the well-known harmful relationships existing between the dyshomeostasis and mis-management of metals and AD onset, we surveyed the experimental work reported in the literature, which deals with the repositioning of metal-chelating drugs in the field of neurodegenerative diseases. The reviewed papers were retrieved from common literature and their selection was limited to those describing the biomolecular aspects associated with neuroprotection. In particular, we emphasized the copper(II) coordination abilities of the selected drugs. Results: Copper, together with zinc and iron, are known to play a key role in regulating neuronal functions. Changes in copper homeostasis are crucial for several neurodegenerative disorders. The studies included in this review may provide an overview on the current strategies aimed at repurposing copper (II) chelating drugs for the treatment of neurodegenerative disorders. Starting from the exemplary case of clioquinol repurposing, we discuss the challenge and the opportunities that repurposing of other metal-chelating drugs may provide (e.g. PBT-2, metformin and cyclodipeptides) in the treatment of neurodegenerative disease. Conclusions: In order to improve the success rate of drug repositioning, comprehensive studies on the molecular mechanism and therapeutic efficacy are still required. The present review upholds that drug repurposing makes significant advantages over drug discovery since repositioned drugs had already passed the safety and toxicity tests. Promising drug candidates in neurodegenerative diseases may be represented by copper chelating classes of drugs, provided that sufficient details on their mechanism of action are available to encourage further investigations and clinical trials.

scholarly journals Drug Repurposing (DR): An Emerging Approach in Drug Discovery

2020 ◽  
Author(s):  
Mithun Rudrapal ◽  
Shubham J. Khairnar ◽  
Anil G. Jadhav
Keyword(s):  
Drug Discovery ◽  
De Novo ◽  
Drug Repositioning ◽  
Development Program ◽  
Drug Repurposing ◽  
New Drugs ◽  
Time Saving ◽  
Biological Targets ◽  
Drug Molecules ◽  
Traditional Drug

Drug repurposing (DR) (also known as drug repositioning) is a process of identifying new therapeutic use(s) for old/existing/available drugs. It is an effective strategy in discovering or developing drug molecules with new pharmacological/therapeutic indications. In recent years, many pharmaceutical companies are developing new drugs with the discovery of novel biological targets by applying the drug repositioning strategy in drug discovery and development program. This strategy is highly efficient, time saving, low-cost and minimum risk of failure. It maximizes the therapeutic value of a drug and consequently increases the success rate. Thus, drug repositioning is an effective alternative approach to traditional drug discovery process. Finding new molecular entities (NME) by traditional or de novo approach of drug discovery is a lengthy, time consuming and expensive venture. Drug repositioning utilizes the combined efforts of activity-based or experimental and in silico-based or computational approaches to develop/identify the new uses of drug molecules on a rational basis. It is, therefore, believed to be an emerging strategy where existing medicines, having already been tested safe in humans, are redirected based on a valid target molecule to combat particularly, rare, difficult-to-treat diseases and neglected diseases.

scholarly journals Teaching an Old Molecule New Tricks: Drug Repositioning for Duchenne Muscular Dystrophy

2019 ◽  
Vol 20 (23) ◽  
pp. 6053 ◽  
Author(s):  
Vitiello ◽  
Tibaudo ◽  
Pegoraro ◽  
Bello ◽  
Canton
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
State Of The Art ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Biological Molecules ◽  
New Drugs ◽  
Dystrophin Deficiency ◽  
Pass Through ◽  
Pathogenic Effects

: Duchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies. The disease is caused by the lack of dystrophin, a structurally essential protein; hence, a definitive cure would necessarily have to pass through some form of gene and/or cell therapy. Cell- and genetic-based therapeutics for DMD have been explored since the 1990s and recently, two of the latter have been approved for clinical use, but their efficacy is still very low. In parallel, there have been great ongoing efforts aimed at targeting the downstream pathogenic effects of dystrophin deficiency using classical pharmacological approaches, with synthetic or biological molecules. However, as it is always the case with rare diseases, R&D costs for new drugs can represent a major hurdle for researchers and patients alike. This problem can be greatly alleviated by experimenting the use of molecules that had originally been developed for different conditions, a process known as drug repurposing or drug repositioning. In this review, we will describe the state of the art of such an approach for DMD, both in the context of clinical trials and pre-clinical studies.

Identification of New Inhibitors for Klebsiella Pneumoniae Trimethoprim-Resistant Dihydrofolate Reductase: An in Silico Drug Repurposing Study

2021 ◽  
Author(s):  
Mostafa Khedrinia ◽  
Farzad Khademi ◽  
Seyed Ali Mirhosseini ◽  
Ramezan Ali Taheri
Keyword(s):  
Klebsiella Pneumoniae ◽  
Dihydrofolate Reductase ◽  
Blood Stream Infection ◽  
Drug Repurposing ◽  
Blood Stream ◽  
New Drugs ◽  
Data Set ◽  
Wide Range ◽  
Approved Drugs ◽  
Dynamics Simulations

Abstract Klebsiella pneumoniae is a gram-negative, non-motile, rod-shaped, and pathogenic bacterium that is widely mutated and resistant to antibiotics. It can cause a wide range of hospital infections such as pneumonia, urinary tract infection, and blood-stream infection in humans. Identification and development of potential drugs due to high drug resistance by Klebsiella pneumoniae are inevitable. Dihydrofolate reductase is a vital enzyme for cells because it converts 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate. Trimethoprim (TMP) is an inhibitor of K. pneumoniae DHFR and other micro-organisms, but resistance to its action develops quickly when it is used. Identifying and designing new drugs is a costly, time-consuming, and challenging process. On the other hand, computational drug repurposing has become an efficient, economical and riskless strategy. In this study, the structure-based virtual docking approach was used to screen the FDA-approved drugs data-set against K. pneumoniae trimethoprim-resistance DHFR to identify potential hit compounds. Then, to validate the hit compounds, molecular dynamics simulations and MM/PBSA analyses were carried out. Our computational drug repurposing results show that the Olodaterol and Pazopanib like reference ligand interact with key residues such as Ile20, Glu27, Phe31, Met50, Leu53 and inhibit K. pneumoniae trimethoprim-resistant dihydrofolate reductase while TMP does not have strong interaction with the active site. According to the results of the current study and since it was based on drug repurposing both compounds of Pazopanib and Olodaterol could be evaluated in phase 2 clinical trials.

scholarly journals Recent Advances in Repurposing Disulfiram and Disulfiram Derivatives as Copper-Dependent Anticancer Agents

2021 ◽  
Vol 8 ◽  
Author(s):  
Vinodh Kannappan ◽  
Misha Ali ◽  
Benjamin Small ◽  
Gowtham Rajendran ◽  
Salena Elzhenni ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Molecular Targets ◽  
Cancer Therapeutics ◽  
New Drugs ◽  
Cancer Clinical Trials ◽  
Anticancer Efficacy ◽  
Wide Range

Copper (Cu) plays a pivotal role in cancer progression by acting as a co-factor that regulates the activity of many enzymes and structural proteins in cancer cells. Therefore, Cu-based complexes have been investigated as novel anticancer metallodrugs and are considered as a complementary strategy for currently used platinum agents with undesirable general toxicity. Due to the high failure rate and increased cost of new drugs, there is a global drive towards the repositioning of known drugs for cancer treatment in recent years. Disulfiram (DSF) is a first-line antialcoholism drug used in clinics for more than 65 yr. In combination with Cu, it has shown great potential as an anticancer drug by targeting a wide range of cancers. The reaction between DSF and Cu ions forms a copper diethyldithiocarbamate complex (Cu(DDC)2 also known as CuET) which is the active, potent anticancer ingredient through inhibition of NF-κB and ubiquitin-proteasome system as well as alteration of the intracellular reactive oxygen species (ROS). Importantly, DSF/Cu inhibits several molecular targets related to drug resistance, stemness, angiogenesis and metastasis and is thus considered as a novel strategy for overcoming tumour recurrence and relapse in patients. Despite its excellent anticancer efficacy, DSF has proven unsuccessful in several cancer clinical trials. This is likely due to the poor stability, rapid metabolism and/or short plasma half-life of the currently used oral version of DSF and the inability to form Cu(DDC)2 at relevant concentrations in tumour tissues. Here, we summarize the scientific rationale, molecular targets, and mechanisms of action of DSF/Cu in cancer cells and the outcomes of oral DSF ± Cu in cancer clinical trials. We will focus on the novel insights on harnessing the immune system and hypoxic microenvironment using DSF/Cu complex and discuss the emerging delivery strategies that can overcome the shortcomings of DSF-based anticancer therapies and provide opportunities for translation of DSF/Cu or its Cu(DDC)2 complex into cancer therapeutics.

Critical analysis and comparison of the side-effect and safety profiles of the new antipsychotics*

1999 ◽  
Vol 174 (S38) ◽  
pp. 34-43 ◽  
Author(s):  
Thomas R. E. Barnes ◽  
Mike A. McPhillips
Keyword(s):  
Side Effects ◽  
Side Effect ◽  
Atypical Antipsychotics ◽  
Antipsychotic Drugs ◽  
Individual Case ◽  
New Drugs ◽  
Risks And Benefits ◽  
Conventional Antipsychotics ◽  
Wide Range ◽  
New Antipsychotics

The conventional antipsychotic drugs are associated with a wide range of unwanted effects (Barnes & Guy Edwards, 1993; Guy Edwards & Barnes, 1993). These side-effects represent part of the burden of patients given antipsychotic medication, affect compliance with treatment, and contribute to the prescribing clinician's weigh-ing-up of the risks and benefits of a particular antipsychotic in an individual case. The conventional drugs show differences in their side-effect profiles, particularly with regard to sedation and extrapyramidal problems, and it is probably a reasonable generalisation to state that these have largely governed clinicians' choice. The newer ‘atypical’ antipsychotics (such as clozapine, risperidone, sertindole, olanzapine, quetiapine and amisulpride) are less liable to cause extrapyramidal symptoms than the conventional antipsychotics. However, this advantage is greater for some of the new drugs than for others, and their safety profiles also differ in other key respects. Thus, in terms of side-effects and safety, each of these newer drugs must be evaluated individually.

A fuzzy logic-based computational method for the repurposing of drugs against COVID-19

Bioimpacts ◽  
2021 ◽  
Author(s):  
Yosef Masoudi-Sobhanzadeh ◽  
Hosein Esmaeili ◽  
Ali Masoudi-Nejad
Keyword(s):  
Fuzzy Logic ◽  
Real World ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Similarity Score ◽  
Emerging Diseases ◽  
Amino Acid Sequences ◽  
Computational Method ◽  
The Real ◽  
Wide Range

Introduction: COVID-19 has spread out all around the world and seriously interrupted human activities. Being a newfound disease, not only many aspects of the disease are unknown, but also there is not an effective medication to cure the disease. Besides, designing a drug is a time-consuming process and needs large investment. Hence, drug repurposing techniques, employed to discover the hidden benefits of the existing drugs, maybe a useful option for treating COVID-19. Methods: The present study exploits the drug repositioning concepts and introduces some candidate drugs which may be effective in controlling COVID-19. The suggested method consists of three main steps. First, the required data such as the amino acid sequences of targets and drug-target interactions are extracted from the public databases. Second, the similarity score between the targets (protein/enzymes) and genome of SARS-COV-2 is computed using the proposed fuzzy logic-based method. Since the classical approaches yield outcomes which may not be useful for the real-world applications, the fuzzy technique can address the issue. Third, after ranking targets based on the obtained scores, the usefulness of drugs affecting them is examined for managing COVID-19. Results: The results indicate that antiviral medicines, designed for curing hepatitis C, may also cure COVID-19. According to the findings, ribavirin, simeprevir, danoprevir, and XTL-6865 may be helpful in controlling the disease. Conclusion: It can be concluded that the similarity-based drug repurposing techniques may be the most suitable option for managing emerging diseases such as COVID-19 and can be applied to a wide range of data. Also, fuzzy logic-based scoring methods can produce outcomes which are more consistent with the real-world biological applications than others.

Molecular Topology and Other Promiscuity Determinants as Predictors of Therapeutic Class - A Theoretical Framework to Guide Drug Repositioning?

2018 ◽  
Vol 18 (13) ◽  
pp. 1110-1122 ◽  
Author(s):  
Juan F. Morales ◽  
Lucas N. Alberca ◽  
Sara Chuguransky ◽  
Mauricio E. Di Ianni ◽  
Alan Talevi ◽  
...  
Keyword(s):  
Molecular Descriptors ◽  
Drug Repositioning ◽  
Drug Repurposing ◽  
Topological Descriptors ◽  
Log P ◽  
Acidity Constant ◽  
Molecular Topology ◽  
Clustering Methods ◽  
Mean Values ◽  
Qsar Models

Much interest has been paid in the last decade on molecular predictors of promiscuity, including molecular weight, log P, molecular complexity, acidity constant and molecular topology, with correlations between promiscuity and those descriptors seemingly being context-dependent. It has been observed that certain therapeutic categories (e.g. mood disorders therapies) display a tendency to include multi-target agents (i.e. selective non-selectivity). Numerous QSAR models based on topological descriptors suggest that the topology of a given drug could be used to infer its therapeutic applications. Here, we have used descriptive statistics to explore the distribution of molecular topology descriptors and other promiscuity predictors across different therapeutic categories. Working with the publicly available ChEMBL database and 14 molecular descriptors, both hierarchical and non-hierchical clustering methods were applied to the descriptors mean values of the therapeutic categories after the refinement of the database (770 drugs grouped into 34 therapeutic categories). On the other hand, another publicly available database (repoDB) was used to retrieve cases of clinically-approved drug repositioning examples that could be classified into the therapeutic categories considered by the aforementioned clusters (111 cases), and the correspondence between the two studies was evaluated. Interestingly, a 3- cluster hierarchical clustering scheme based on only 14 molecular descriptors linked to promiscuity seem to explain up to 82.9% of approved cases of drug repurposing retrieved of repoDB. Therapeutic categories seem to display distinctive molecular patterns, which could be used as a basis for drug screening and drug design campaigns, and to unveil drug repurposing opportunities between particular therapeutic categories.

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