J Clin Pharm Ther. 2022 Oct 6. doi: 10.1111/jcpt.13787. Online ahead of print.

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: Acinetobacter baumannii is one of the most important nosocomial pathogens with the ability to cause infections such as meningitis, pneumonia, urinary tract, septicaemia and wound infections. A wide range of virulence factors are responsible for pathogenesis and high mortality of A. baumannii including outer membrane proteins, lipopolysaccharide, capsule, phospholipase, nutrient- acquisition systems, efflux pumps, protein secretion systems, quarom sensing and biofilm production. These virulence factors contribute in pathogen survival in stressful conditions and antimicrobial resistance.

COMMENT: According to the World Health Organization (WHO), A. baumannii is one of the most resistant pathogens of ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, A. baumannii, Pseudomonas aeruginosa and Enterobacter spp.). In recent years, resistance to a wide range of antibiotics in A. baumannii has significantly increased and the high emergence of extensively drug resistant (XDR) isolates is challenging. Among therapeutic antibiotics, resistance to tigecycline as a last resort antibiotic has become a global concern. Several mechanisms are involved in tigecycline resistance, the most important of which is RND (Resistance-Nodulation-Division) family efflux pumps overexpression. The development of new therapeutic strategies to confront A. baumannii infections has been very promising in recent years.

WHAT IS NEW AND CONCLUSION: In the present review we highlight microbiological and virulence traits in A. baumannii and peruse the tigecycline resistance mechanisms and novel therapeutic options. Among the novel therapeutic strategies we focus on combination therapy, drug repurposing, novel antibiotics, bacteriophage therapy, antimicrobial peptides (AMPs), human monoclonal antibodies (Hu-mAbs), nanoparticles and gene editing.

PMID:36200470 | DOI:10.1111/jcpt.13787

Curr Med Chem. 2022 Oct 4. doi: 10.2174/0929867329666221004104430. Online ahead of print.

ABSTRACT

BACKGROUND: In the last few years in silico tools, including drug repurposing coupled with structure-based virtual screening, have been extensively employed to look for anti-COVID-19 agents.

OBJECTIVE: The present review aims to provide readers with a portrayal of computational approaches that could conduct more quickly and cheaply to novel anti-viral agents. Particular attention is given to docking-based virtual screening.

METHOD: The World Health Organization website was consulted to gain the latest information on SARS-CoV-2, its novel variants and their interplay with COVID-19 severity and treatment options. The Protein Data Bank was explored to look for 3D coordinates of SARS-CoV-2 proteins in their free and bound states, in the wild-types and mutated forms. Recent literature related to in silico studies focused on SARS-CoV-2 proteins was searched through PubMed.

RESULTS: A large amount of work has been devoted thus far to computationally targeting viral entry and searching for inhibitors of the S-protein/ACE2 receptor complex. Another large area of investigation is linked to in silico identification of molecules able to block viral proteases -including Mpro- thus avoiding maturation of proteins crucial for virus life cycle. Such computational studies have explored the inhibitory potential of the most diverse molecule databases (including plant extracts, dietary compounds, FDA approved drugs).

CONCLUSION: More efforts need to be dedicated in the close future to experimentally validate the therapeutic power of in silico identified compounds in order to catch, among the wide ensemble of computational hits, novel therapeutics to prevent and/or treat COVID-19.

PMID:36200217 | DOI:10.2174/0929867329666221004104430

Reprod Toxicol. 2022 Oct 2:S0890-6238(22)00142-3. doi: 10.1016/j.reprotox.2022.09.008. Online ahead of print.

ABSTRACT

Since COVID-19 began in 2019, therapeutic agents are being developed for its treatment. Among the numerous potential therapeutic agents, ritonavir (RTV), an anti-viral agent, has recently been identified as an important element of the COVID-19 treatment. Moreover, RTV has also been applied in the drug repurposing of cancer cells. However, previous studies have shown that RTV has toxic effects on various cell types. In addition, RTV regulates AKT phosphorylation within cancer cells, and AKT is known to control sperm functions (motility, capacitation, and so on). Although deleterious effects of RTV have been reported, it is not known whether RTV has male reproduction toxicity. Therefore, in this study, we aimed to investigate the effects of RTV on sperm function and male fertility. In the present study, sperm collected from the cauda epididymis of mice were incubated with various concentrations of RTV (0, 0.1, 1, 10, and 100μM). The expression levels of AKT, phospho-AKT (Thr308 and Ser473), and phospho-tyrosine proteins, sperm motility, motion kinematics, capacitation status, and cell viability were assessed after capacitation. The results revealed that AKT phosphorylation at Thr308 and Ser473 was significantly increased, and the levels of tyrosine-phosphorylated proteins (at approximately 25 and 100kDa) were significantly increased in a dose-dependent manner. In addition, RTV adversely affected sperm motility, motion kinematics, and cell viability. Taken together, RTV may have negative effects on sperm function through an abnormal increase in tyrosine phosphorylation and phospho-AKT levels. Therefore, individuals taking or prescribing RTV should be aware of its reproductive toxicity.

PMID:36198369 | DOI:10.1016/j.reprotox.2022.09.008

Eur J Pharm Biopharm. 2022 Oct 2:S0939-6411(22)00219-3. doi: 10.1016/j.ejpb.2022.09.024. Online ahead of print.

ABSTRACT

Melanoma is the most malignant form of skin cancer across the globe. Conventional therapies are currently ineffective which could be attributed to the rampant chemo-resistance, metastasis, inability to cross the skin barriers and accumulate within the tumor microenvironment. This advent brings in the principles of drug repurposing by repositioning Niclosamide (NIC), an anthelmintic drug for skin cancer. Incorporation into the liposomes facilitated enhanced melanoma cell uptake and apoptosis. Cytotoxicity studies revealed 1.756-fold enhancement in SK-MEL-28 cytotoxicity by NIC-loaded liposomes compared to free drug. Qualitative and quantitative cell internalization indicated greater drug uptake within the melanoma cells illustrating the efficacy of liposomes as efficient carrier systems. Nuclear staining showed blebbing and membrane shrinkage. Elevated ROS levels and apoptosis shown by DCFDA and acridine orange-ethidium bromide staining revealed greater melanoma cell death by liposomes compared to free drug. Incorporating NIC liposomes into the thermogel system restricted the liposomes as a depot onto the upper skin layers. Sustained zero order release up to 48 h with liposomes and 23.58-fold increase in viscosity led to the sol-to-gel transition at 33℃ was observed with liposomal thermogel. Ex vivo gel permeation studies revealed that C-6 loaded liposomes incorporated within the thermogel successfully formed a depot over the upper skin layer for 6 h to prevent transdermal delivery and systemic adverse effects. Thus, it could be concluded that NIC loaded liposomal thermogel system could be an efficacious therapeutic alternative for the management of melanoma.

PMID:36198344 | DOI:10.1016/j.ejpb.2022.09.024

IEEE/ACM Trans Comput Biol Bioinform. 2022 Oct 5;PP. doi: 10.1109/TCBB.2022.3212051. Online ahead of print.

ABSTRACT

Computational drug repositioning technology is an effective tool to accelerate drug development. Although this technique has been widely used and successful in recent decades, many existing models still suffer from multiple drawbacks such as the massive number of unvalidated drug-disease associations and the inner product. The limitations of these works are mainly due to the following two reasons: firstly, previous works used negative sampling techniques to treat unvalidated drug-disease associations as negative samples, which is invalid in real-world settings; secondly, the inner product cannot fully take into account the feature information contained in the latent factor of drug and disease. In this paper, we propose a novel PUON framework for addressing the above deficiencies, which models the risk estimator of computational drug repositioning only using validated (Positive) and unvalidated (Unlabelled) drug-disease associations without employing negative sampling techniques. The PUON also proposed an Outer Neighborhood-based classifier for modeling the cross-feature information of the latent facotor. For a comprehensive comparison, we considered 6 popular baselines. Extensive experiments in four real-world datasets showed that PUON model achieved the best performance based on 6 evaluation metrics.

PMID:36197871 | DOI:10.1109/TCBB.2022.3212051

Chem Commun (Camb). 2022 Oct 5. doi: 10.1039/d2cc03135c. Online ahead of print.

ABSTRACT

The single-stranded RNA genome of SARS-CoV-2 contains some G-quadruplex-forming G-rich elements which are putative drug targets. Here, we performed a ligand-based pharmacophore virtual screening of FDA approved drugs to find candidates targeting such RNA structures. Further in silico and in vitro assays identified three drugs as emerging SARS-CoV-2 RNA G-quadruplex binders.

PMID:36196950 | DOI:10.1039/d2cc03135c

Expert Rev Clin Pharmacol. 2022 Oct 5. doi: 10.1080/17512433.2022.2132226. Online ahead of print.

ABSTRACT

INTRODUCTION: Drug repurposing represented an important contribution in the management of COVID-19, becoming the first line of defense to mitigate the effects of the new coronavirus. In a brief time, drug repurposing (DR) provided potentially effective and already available drugs for COVID-19, while specific therapies against SARS-CoV-2 and/or vaccines were developing. Identifying repurposed drugs requires a multidisciplinary approach, where clinical pharmacology represents the missing piece of the puzzle.

AREAS COVERED: Nowadays, clinical pharmacology is recognized as a discipline at the core of translational science, whose activities lead to the identification of the right drug for the right patient. In the context of the COVID-19 pandemic, its role in drug development and therapy choice has been decisive and itself repositioned. In this review, we tried to highlight the important role of clinical pharmacology in the identification and evaluation of possible repurposed drugs for COVID-19.

EXPERT OPINION: We believe that clinical pharmacology had an important role in identifying patient-oriented therapy during the COVID-19 pandemic. In this context, DR was just one of the challenges for clinical pharmacology, which proved that this discipline is ready to respond to future threats.

PMID:36196903 | DOI:10.1080/17512433.2022.2132226

Pharm Res. 2022 Oct 4. doi: 10.1007/s11095-022-03399-4. Online ahead of print.

ABSTRACT

PURPOSE: Glioblastoma multiforme (GBM) is a grade IV, highly proliferative, and malignant form of brain tumor with a 5-year survival rate at ~ 5%. Current treatment strategies for GBM include surgery, radiation, and chemotherapy. Major challenges in GBM management include difficulties in surgical resection due to brain's vital functions and GBM metastasis, development of resistance to temozolomide (TMZ), and protection of tumor by blood brain barrier (BBB). Therefore, we aimed to discover a novel therapeutic for GBM by targeting its metabolic reprogramming.

METHOD: We screened metabolic inhibitors by their effects on GBM cell viability by MTT assay. We discovered an FDA-approved drug stiripentol (STP) in our screening of metabolic inhibitors in GBM cells. STP is used for Dravet syndrome (a rare epilepsy). We further tested efficacy of STP using proliferation assay, clonogenic assay, in vitro migration assay, cell cycle assay, apoptosis assay, and in U87 3D spheroids. We also tested the toxicity of STP, and combinations used in the study on normal human dermal fibroblasts.

RESULTS: STP was effective in decreasing GBM cell viability, proliferation, clonogenic ability, and migration. Moreover, cell cycle changes were involved but robust apoptosis was absent in STP's anticancer effects. STP was effective in 3D spheroid models, and in TMZ-resistant cells. STP showed additive or synergistic effect with TMZ in different anticancer assays on GBM cells and was considerably less toxic in normal cells.

CONCLUSION: Our results indicate that STP can be an effective GBM therapeutic that enhances the effects of TMZ on GBM cells. Importantly, STP reduced viability of TMZ-resistant cells. Our results warrant further studies in the mechanistic basis of STP's effects on GBM cells and the preclinical potential of STP in animal models.

PMID:36195821 | DOI:10.1007/s11095-022-03399-4

Cell Death Dis. 2022 Oct 3;13(10):846. doi: 10.1038/s41419-022-05250-5.

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic. Of particular interest for this topic are the signaling cascades that regulate cell survival and death, two opposite cell programs whose control is hijacked by viral infections. The AKT and the Unfolded Protein Response (UPR) pathways, which maintain cell homeostasis by regulating these two programs, have been shown to be deregulated during SARS-CoVs infection as well as in the development of cancer, one of the most important comorbidities in relation to COVID-19. Recent evidence revealed two way crosstalk mechanisms between the AKT and the UPR pathways, suggesting that they might constitute a unified homeostatic control system. Here, we review the role of the AKT and UPR pathways and their interaction in relation to SARS-CoV-2 infection as well as in tumor onset and progression. Feedback regulation between AKT and UPR pathways emerges as a master control mechanism of cell decision making in terms of survival or death and therefore represents a key potential target for developing treatments for both viral infection and cancer. In particular, drug repositioning, the investigation of existing drugs for new therapeutic purposes, could significantly reduce time and costs compared to de novo drug discovery.

PMID:36192392 | DOI:10.1038/s41419-022-05250-5

Anticancer Res. 2022 Oct;42(10):4727-4733. doi: 10.21873/anticanres.15977.

ABSTRACT

BACKGROUND/AIM: The development of pharmacological inhibitors targeting negative regulators of p53, such as murine double minute (MDM) 2 and, more recently, MDM4, has been actively pursued as a potential strategy to treat cancers with wild-type p53. We previously showed that CEP-1347, a small molecule kinase inhibitor originally developed for the treatment of Parkinson's disease, suppressed MDM4 expression and activated wild-type p53 in retinoblastoma cells. However, it remains unknown whether CEP-1347 acts as an MDM4 inhibitor and as such activates p53 in other types of human cancer cells.

MATERIALS AND METHODS: The effects of CEP-1347 and MDM4 knockdown on the mRNA and protein expression of components of the p53 pathway, including MDM4, in human glioma cell lines with and without p53 mutation were examined by RT-PCR and western blot analyses. Trypan blue dye exclusion was used to examine the effect of CEP-1347 on cell growth.

RESULTS: CEP-1347 decreased the expression of MDM4, increase that of p53, and activated the p53 pathway in glioma cells with wild-type p53. Knockdown-mediated inhibition of MDM4 expression in a glioma cell line with wild-type p53 that overexpresses MDM4 resulted in increased p53 expression and activation of the p53 pathway. CEP-1347 preferentially inhibited the growth of glioma cells with wild-type p53 without showing toxicity to normal cells at clinically relevant concentrations.

CONCLUSION: Our findings suggest CEP-1347 is a novel inhibitor of MDM4 protein expression and as such activates p53 to inhibit the growth of cancer cells with wild-type p53, including retinoblastoma and glioblastoma.

PMID:36192008 | DOI:10.21873/anticanres.15977

Iran J Sci Technol Trans A Sci. 2022 Sep 24:1-9. doi: 10.1007/s40995-022-01364-9. Online ahead of print.

ABSTRACT

The treatment of COVID-19 disease has been one of the most critical essential concerns of researchers in recent years. One of the most exciting and potential therapeutic targets for SARS-CoV-2 therapy progression is RNA-dependent RNA polymerase (RdRP), a viral enzyme for viral RNA replication throughout host cells. According to some research, Remdesivir suppresses RdRp. The nucleoside medication remdesivir has been authorized under an Emergency Use Authorization to treat COVID-19. Given the role of this enzyme in virus replication, our scientific question is whether Remdesivir is the most appropriate antiviral drug to inhibit this enzyme or not. Accordingly, this study aimed to repurpose antiviral drugs to inhibition of RdRp using virtual screening and Molecular Dynamics simulation methods. Five FDA-approved antiviral medications, including Elbasvir, Glecaprevir, Ledipasvir, Paritaprevir, and Simeprevir, had good interaction potential with RdRp. Also, the results show that the number of H-bonds and contacts and ∆G interactions between the protein and ligand in the Remdesivir complex is less than those of other complexes. According to the given data which shows the tendency of binding with RdRp for Paritaprevir, Simeprevir, Glecaprevir, and Ledipasvir and Elbasvir is more than Remdesivir and due to the fact that these five drugs have a high tendency to bind to other targets in the SARS-CoV-2, the use of Remdesivir as an antiviral drug in the treatment of COVID-19 should be considered more sensitively.

PMID:36187298 | PMC:PMC9510211 | DOI:10.1007/s40995-022-01364-9

Front Med (Lausanne). 2022 Sep 15;9:965429. doi: 10.3389/fmed.2022.965429. eCollection 2022.

ABSTRACT

Bone metastasis is a common and devastating consequence of several major cancer types, including breast and prostate. Osteocytes are the predominant bone cell, and through connexin (Cx) 43 hemichannels release ATP to the bone microenvironment that can be hydrolyzed to adenosine. Here, we investigated how genes related to ATP paracrine signaling are involved in two common bone-metastasizing malignancies, estrogen receptor positive (ER+) breast and prostate cancers. Compared to other sites, bone metastases of both cancer types expressed higher levels of ENTPD1 and NT5E, which encode CD39 and CD73, respectively, and hydrolyze ATP to adenosine. ADORA3, encoding the adenosine A3 receptor, had a similar expression pattern. In primary ER+ breast cancer, high levels of the triplet ENTPD1/NT5E/ADORA3 expression signature was correlated with lower overall, distant metastasis-free, and progression-free survival. In ER+ bone metastasis biopsies, this expression signature is associated with lower survival. This expression signature was also higher in bone-metastasizing primary prostate cancers than in those that caused other tumor events or did not lead to progressive disease. In 3D culture, a non-hydrolyzable ATP analog inhibited the growth of breast and prostate cancer cell lines more than ATP did. A3 inhibition also reduced spheroid growth. Large-scale screens by the Drug Repurposing Hub found ER+ breast cancer cell lines were uniquely sensitive to adenosine receptor antagonists. Together, these data suggest a vital role for extracellular ATP degradation and adenosine receptor signaling in cancer bone metastasis, and this study provides potential diagnostic means for bone metastasis and specific targets for treatment and prevention.

PMID:36186774 | PMC:PMC9520286 | DOI:10.3389/fmed.2022.965429

Front Oncol. 2022 Sep 15;12:940582. doi: 10.3389/fonc.2022.940582. eCollection 2022.

ABSTRACT

Beta-blockers are currently studied to improve therapeutic options for patients with angiosarcoma. However, most of these patients have no cardiovascular co-morbidity and it is therefore crucial to discuss the most optimal pharmacological properties of beta-blockers for this population. To maximize the possible effectiveness in angiosarcoma, the use of a non-selective beta-blocker is preferred based on in vitro data. To minimize the risk of cardiovascular adverse events a beta-blocker should ideally have intrinsic sympathomimetic activity or vasodilator effects, e.g. labetalol, pindolol or carvedilol. However, except for one case of carvedilol, only efficacy data of propranolol is available. In potential follow-up studies labetalol, pindolol or carvedilol can be considered to reduce the risk of cardiovascular adverse events.

PMID:36185303 | PMC:PMC9520289 | DOI:10.3389/fonc.2022.940582

J Biomol Struct Dyn. 2022 Oct 2:1-8. doi: 10.1080/07391102.2022.2120538. Online ahead of print.

ABSTRACT

The protein galectin, which binds to carbohydrates and is involved in a number of therapeutic processes including cell proliferation, inflammatory responses, apoptosis, etc., has been discovered as a potential therapeutic target. Galectin-3 is a stable biomarker that exhibits both increased and decreased expression in a variety of illnesses and infections, regardless of sex, age, or body mass index. The goal of the current study is to apply bioinformatics techniques to examine the possibility of cardiovascular medications to inhibit Galectin-3-related biological activities. Unsupervised clustering techniques, molecular docking, and guided molecular dynamics (MD) simulation were used to create a computational pipeline that was used to screen potential chemical compounds from a library of chemical compounds with related molecular fingerprints. Utilizing input factors such as gene expression, mode of action, and chemical descriptors, clustering enables prioritization of medicinal molecules. Twenty-four compounds were screened and repurposed against Galectin-3 utilizing molecular docking as part of the cluster-facilitated virtual screening technique. The polar interactions that Arg144, Glu184, Arg162, His158, and Asn174 have with Bufalin, Cymarin, and Ouabalin have the highest binding affinities, according to docking studies. Studies using MD simulations confirm the tested compounds' ability to inhibit Galectin-3. Galactin-3 targeted experimental and in vivo animal model-based validation studies using Bufalin, Cymarin, and Ouabalin are also necessary.Communicated by Ramaswamy H. Sarma.

PMID:36184598 | DOI:10.1080/07391102.2022.2120538

ChemMedChem. 2022 Oct 2. doi: 10.1002/cmdc.202200399. Online ahead of print.

ABSTRACT

Repurposing of antiviral drugs affords a rapid and effective strategy to develop therapies to counter pandemics such as COVID-19. SARS-CoV-2 replication is closely linked to the metabolism of cytosine-containing nucleotides, especially cytidine-5' -triphosphate (CTP), such that the integrity of the viral genome is highly sensitive to intracellular CTP levels. CTP synthase (CTPS) catalyzes the rate-limiting step for the de novo biosynthesis of CTP. Hence, it is of interest to know the effects of the 5' -triphosphate (TP) metabolites of repurposed antiviral agents on CTPS activity. Using E. coli CTPS as a model enzyme, we show that ribavirin-5' -TP is a weak allosteric activator of CTPS, while sofosbuvir-5' -TP and adenine-arabinofuranoside-5 ' -TP are both substrates. β-D-N 4 -Hydroxycytidine-5' -TP is a weak competitive inhibitor relative to CTP, but induces filament formation by CTPS. Alternatively, sofosbuvir-5' -TP prevented CTP-induced filament formation. These results reveal the underlying potential for repurposed antivirals to affect the activity of a critical pyrimidine nucleotide biosynthetic enzyme.

PMID:36184568 | DOI:10.1002/cmdc.202200399

Yakugaku Zasshi. 2022;142(10):1037-1044. doi: 10.1248/yakushi.22-00121.

ABSTRACT

Epalrestat is the only aldose reductase inhibitor that is currently available for diabetic peripheral neuropathy. Oxidative stress impairs endothelial cells, thereby leading to numerous pathological conditions. Increasing antioxidative ability is important to prevent cellular toxicity induced by reactive oxygen species. Epalrestat increases antioxidant defense factors such as glutathione and γ-glutamylcysteine ligase in vascular endothelial cells through activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). This increases suppression of oxidative stress-induced cellular toxicity. Cadmium is an industrial and environmental pollutant that targets the vascular endothelium. The vascular system is critically affected by cadmium toxicity. Therapeutic treatment against cadmium toxicity is chelation therapy that promotes metal excretion; however, cadmium chelators can cause renal toxicity. Therefore, safe and efficient therapeutic agents are required. Epalrestat suppresses cadmium-induced cytotoxicity in vascular endothelial cells through activation of Nrf2. In addition, epalrestat affects the intracellular levels of cadmium, cadmium transporter Zrt-Irt-like protein 8 (ZIP8), and metallothionein (MT). The upregulation of ZIP8 and MT may be involved in the suppression of cadmium-induced cytotoxicity by epalrestat. Drug repurposing is a new strategy for drug discovery in which the pharmacological action of existing medicines whose safety and pharmacokinetics have already been confirmed clinically and whose use has been approved is examined comprehensively at the molecular level. The results can be applied to the development of existing drugs for use as medicines for the treatment of other diseases. This review provides useful findings for future expansion of indications as research leading to drug repurposing of epalrestat.

PMID:36184437 | DOI:10.1248/yakushi.22-00121

Bioorg Med Chem. 2022 Sep 28;73:117036. doi: 10.1016/j.bmc.2022.117036. Online ahead of print.

ABSTRACT

Monkeypox disease is a zoonosis that has the monkey virus (MPXV) as its etiologic agent, an enveloped double-stranded DNA virus that has caused some severe cases, leading to 3-6% fatality ratio. MPXV exhibits similar symptoms to those observed for Smallpox infection. Human-to-human transmission occurs via droplet respiratory particles and close contact with skin lesions of an infected person or recently contaminated objects. MPXV symptoms include fever, intense headache, back pain, myalgia, severe asthenia, lymphadenopathy, and skin eruption. The 2022 outbreak is growing, spreading over 75 countries/territories. Based on this, the MPXV outbreak was declared a "public health emergency of international concern" by WHO. In 2019, a vaccine-based modified attenuated vaccinia virus (Ankara strain) was approved for MPXV prevention. However, its availability remains limited. Besides, there are no approved or licensed drugs to treat MPXV currently. However, tecovirimat was licensed by the European Medicines Agency (EMA) to treat MPXV infections. Notwithstanding all these aspects and limitations associated with MPXV, How the medicinal chemistry could help us?

PMID:36183614 | DOI:10.1016/j.bmc.2022.117036

BioData Min. 2022 Oct 1;15(1):25. doi: 10.1186/s13040-022-00307-9.

ABSTRACT

The expanding body of potential therapeutic targets requires easily accessible, structured, and transparent real-time interpretation of molecular data. Open-access genomic, proteomic and drug-repurposing databases transformed the landscape of cancer research, but most of them are difficult and time-consuming for casual users. Furthermore, to conduct systematic searches and data retrieval on multiple targets, researchers need the help of an expert bioinformatician, who is not always readily available for smaller research teams. We invite research teams to join and aim to enhance the cooperative work of more experienced groups to harmonize international efforts to overcome devastating malignancies. Here, we integrate available fundamental data and present a novel, open access, data-aggregating, drug repurposing platform, deriving our searches from the entries of Clue.io. We show how we integrated our previous expertise in small-cell lung cancer (SCLC) to initiate a new platform to overcome highly progressive cancers such as triple-negative breast and pancreatic cancer with data-aggregating approaches. Through the front end, the current content of the platform can be further expanded or replaced and users can create their drug-target list to select the clinically most relevant targets for further functional validation assays or drug trials. EZCancerTarget integrates searches from publicly available databases, such as PubChem, DrugBank, PubMed, and EMA, citing up-to-date and relevant literature of every target. Moreover, information on compounds is complemented with biological background information on eligible targets using entities like UniProt, String, and GeneCards, presenting relevant pathways, molecular- and biological function and subcellular localizations of these molecules. Cancer drug discovery requires a convergence of complex, often disparate fields. We present a simple, transparent, and user-friendly drug repurposing software to facilitate the efforts of research groups in the field of cancer research.

PMID:36183137 | DOI:10.1186/s13040-022-00307-9

Cell Biosci. 2022 Oct 1;12(1):165. doi: 10.1186/s13578-022-00899-z.

ABSTRACT

Since an outbreak started in China in 2019, coronavirus disease 2019 (COVID-19) has rapidly become a worldwide epidemic with high contagiousness and caused mass mortalities of infected cases around the world. Currently, available treatments for COVID-19, including supportive care, respiratory support and antiviral therapy, have shown limited efficacy. Thus, more effective therapeutic modalities are highly warranted. Drug repurposing, as an efficient strategy to explore a potential broader scope of the application of approved drugs beyond their original indications, accelerates the process of discovering safe and effective agents for a given disease. Since the outbreak of COVID-19 pandemic, drug repurposing strategy has been widely used to discover potential antiviral agents, and some of these drugs have advanced into clinical trials. Antitumor drugs compromise a vast variety of compounds and exhibit extensive mechanism of action, showing promising properties in drug repurposing. In this review, we revisit the potential value of antitumor drugs in the treatment of COVID-19 and systematically discuss their possible underlying mechanisms of the antiviral actions.

PMID:36182930 | DOI:10.1186/s13578-022-00899-z

Comput Biol Med. 2022 Sep 22;150:106127. doi: 10.1016/j.compbiomed.2022.106127. Online ahead of print.

ABSTRACT

Computational drug repositioning is an effective way to find new indications for existing drugs, thus can accelerate drug development and reduce experimental costs. Recently, various deep learning-based repurposing methods have been established to identify the potential drug-disease associations (DDA). However, effective utilization of the relations of biological entities to capture the biological interactions to enhance the drug-disease association prediction is still challenging. To resolve the above problem, we proposed a heterogeneous graph neural network called REDDA (Relations-Enhanced Drug-Disease Association prediction). Assembled with three attention mechanisms, REDDA can sequentially learn drug/disease representations by a general heterogeneous graph convolutional network-based node embedding block, a topological subnet embedding block, a graph attention block, and a layer attention block. Performance comparisons on our proposed benchmark dataset show that REDDA outperforms 8 advanced drug-disease association prediction methods, achieving relative improvements of 0.76% on the area under the receiver operating characteristic curve (AUC) score and 13.92% on the precision-recall curve (AUPR) score compared to the suboptimal method. On the other benchmark dataset, REDDA also obtains relative improvements of 2.48% on the AUC score and 4.93% on the AUPR score. Specifically, case studies also indicate that REDDA can give valid predictions for the discovery of -new indications for drugs and new therapies for diseases. The overall results provide an inspiring potential for REDDA in the in silico drug development. The proposed benchmark dataset and source code are available in https://github.com/gu-yaowen/REDDA.

PMID:36182762 | DOI:10.1016/j.compbiomed.2022.106127