J Biomed Inform. 2021 Jun 10:103838. doi: 10.1016/j.jbi.2021.103838. Online ahead of print.

ABSTRACT

We aimed to develop and validate a new graph embedding algorithm for embedding drug-disease-target networks to generate novel drug repurposing hypotheses. Our model denotes drugs, diseases and targets as subjects, predicates and objects, respectively. Each entity is represented by a multidimensional vector and the predicate is regarded as a translation vector from a subject to an object vectors. These vectors are optimized so that when a subject-predicate-object triple represents a known drug-disease-target relationship, the summed vector between the subject and the predicate is to be close to that of the object; otherwise, the summed vector is distant from the object. The DTINet dataset was utilized to test this algorithm and discover unknown links between drugs and diseases. In cross-validation experiments, this new algorithm outperformed the original DTINet model. The MRR (Mean Reciprocal Rank) values of our models were around 0.80 while those of the original model were about 0.70. In addition, we have identified and verified several pairs of new therapeutic relations as well as adverse effect relations that were not recorded in the original DTINet dataset. This approach showed excellent performance, and the predicted drug-disease and drug-side-effect relationships were found to be consistent with literature reports. This novel method can be used to analyze diverse types of emerging biomedical and healthcare-related knowledge graphs (KG).

PMID:34119691 | DOI:10.1016/j.jbi.2021.103838

J Infect Public Health. 2021 May 26;14(7):852-862. doi: 10.1016/j.jiph.2021.05.009. Online ahead of print.

ABSTRACT

The ongoing enormous loss of human life owing to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has led to a global crisis ranging from the collapse of health - care systems to socio-economic instability. As SARS-CoV-2 is a novel virus, very little information is available from researchers and therefore, a rigorous effort is required to decode its pathogenicity. There are no licenced treatment options available for treating SARS-CoV-2 infections and the development of a new antiviral drug targeting coronavirus cannot happen soon. Consequently, drug repurposing is a promising solution for combating the present pandemic. In this review, we have thoroughly discussed all the proteins encoded by the SARS-CoV-2 genome; their importance in pathogenicity and their potential role in drug discovery. Also, the budding threat of co-infections by other pathogenic microbes has been highlighted. Furthermore, the advances made in the medicinal field for the treatment and prevention of this viral infection is explained. Altogether, this review will provide some insightful discussions about this infectious disease and will meet certain of the knowledge gaps which exist by presenting an exhaustive and extensive scientific report on the ongoing mission for COVID-19 drug discovery.

PMID:34118735 | DOI:10.1016/j.jiph.2021.05.009

Cardiovasc Res. 2021 Jun 12:cvab202. doi: 10.1093/cvr/cvab202. Online ahead of print.

ABSTRACT

AIMS: Interleukin-1β (IL-1β) is an important pathogenic factor in cardiovascular diseases including chronic heart failure (HF). The CANTOS trial highlighted that inflammasomes as primary sources of IL-1 β are promising new therapeutic targets in cardiovascular diseases. Therefore, we aimed to assess inflammasome activation in failing hearts to identify activation patterns of inflammasome subtypes as sources of IL-1β.

METHODS AND RESULTS: Out of the 4 major inflammasome sensors tested, expression of the inflammasome protein absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) increased in human heart failure regardless of the etiology (ischemic or dilated cardiomyopathy) while the NLRP1/NALP1 and NLRP3 (NLR family, pyrin domain containing 1 and 3) inflammasome showed no change in HF samples. AIM2 expression was primarily detected in monocytes/macrophages of failing hearts. Translational animal models of HF (pressure or volume overload, and permanent coronary artery ligation in rat, as well as ischemia/reperfusion-induced HF in pigs) demonstrated activation pattern of AIM2 similar to that of observed in end-stages of human HF. In vitro AIM2 inflammasome activation in human THP-1 monocytic cells and human AC16 cells was significantly reduced by pharmacological blockade of pannexin-1 channels by the clinically used uricosuric drug probenecid. Probenecid was also able to reduce pressure overload-induced mortality and restore indices of disease severity in a rat chronic HF model in vivo.

CONCLUSIONS: This is the first report showing that AIM2 and NLRC4 inflammasome activation contribute to chronic inflammation in heart failure and that probenecid alleviates chronic HF by reducing inflammasome activation. The present translational study suggests the possibility of repositioning of probenecid for HF indications.

PMID:34117866 | DOI:10.1093/cvr/cvab202

Sci Rep. 2021 Jun 11;11(1):12338. doi: 10.1038/s41598-021-91428-4.

ABSTRACT

Drug development for rare and intractable diseases has been challenging for decades due to the low prevalence and insufficient information on these diseases. Drug repositioning is increasingly being used as a promising option in drug development. We aimed to analyze the trend of drug repositioning and inter-disease drug repositionability among rare and intractable diseases. We created a list of rare and intractable diseases based on the designated diseases in Japan. Drug information extracted from clinical trial data were integrated with information of drug target genes, which represent the mechanism of drug action. We obtained 753 drugs and 551 drug target genes from 8307 clinical trials for 189 diseases or disease groups. Trend analysis of drug sharing between a disease pair revealed that 1676 drug repositioning events occurred in 4401 disease pairs. A score, Rgene, was invented to investigate the proportion of drug target genes shared between a disease pair. Annual changes of Rgene corresponded to the trend of drug repositioning and predicted drug repositioning events occurring within a year or two. Drug target gene-based analyses well visualized the drug repositioning landscape. This approach facilitates drug development for rare and intractable diseases.

PMID:34117295 | DOI:10.1038/s41598-021-91428-4

Comput Biol Med. 2021 Jun 8;134:104538. doi: 10.1016/j.compbiomed.2021.104538. Online ahead of print.

ABSTRACT

The outbreak of COVID-19 disease caused by SARS-CoV-2, along with the lack of targeted medicaments, forced the scientific world to search for new antiviral formulations. In the current emergent situation, drug repurposing of well-known traditional and/or approved drugs could be the most effective strategy. Herein, through computational approaches, we aimed to screen 14 natural compounds from limonoids and terpenoids class for their ability to inhibit the key therapeutic target proteins of SARS-CoV-2. Among these, some limonoids, namely deacetylnomilin, ichangin and nomilin, and the terpenoid β-amyrin provided good interaction energies with SARS-CoV-2 3CL hydrolase (Mpro) in molecular dynamic simulation. Interestingly, deacetylnomilin and ichangin showed direct interaction with the catalytic dyad of the enzyme so supporting their potential role in preventing SARS-CoV-2 replication and growth. On the contrary, despite the good affinity with the spike protein RBD site, all the selected phytochemicals lose contact with the amino acid residues over the course of 120ns-long molecular dynamics simulations therefore suggesting they scarcely can interfere in SARS-CoV-2 binding to the ACE2 receptor. The in silico analyses of docking score and binding energies, along with predicted pharmacokinetic profiles, indicate that these triterpenoids might have potential as inhibitors of SARS-CoV-2 Mpro, recommending further in vitro and in vivo investigations for a complete understanding and confirmation of their inhibitory potential.

PMID:34116362 | DOI:10.1016/j.compbiomed.2021.104538

ACS Infect Dis. 2021 Jun 11. doi: 10.1021/acsinfecdis.1c00139. Online ahead of print.

ABSTRACT

Leishmaniases are vector-borne neglected diseases caused by single-celled parasites. The search for new antileishmanial drugs has experienced a strong boost thanks to the application of bioimaging to phenotypic screenings based on intracellular amastigotes. Mouse splenic explants infected with fluorescent strains of Leishmania are proven tools of drug discovery, where hits can be easily transferred to preclinical in vivo models. We have developed a two-staged platform for antileishmanial drugs. First, we screened two commercial collections of repurposing drugs with a total of 1769 compounds in ex vivo mouse splenocytes infected with an infrared emitting Leishmania infantum strain. The most active and safest compounds were scaled-up to in vivo models of chronic Leishmania donovani visceral leishmaniasis and Leishmania major cutaneous leishmaniasis. From the total of 1769 compounds, 12 hits with selective indices >35 were identified, and 4 of them were tested in vivo in a model of L. donovani visceral leishmaniasis. Nifuratel, a repurposed synthetic nitrofuran, when administered orally at 50 mg/kg bw once or twice a day for 10 days, caused >80% reduction in the parasitic load. Furthermore, the intralesional administration of nifuratel in a model of cutaneous leishmaniasis by L. major produced the parasitological cure. From the previous results we have deduced the great capacity of mouse splenic explants to identify new hits, a model which could be easily transferred to in vivo models, as well as the potential use of nifuratel as an alternative to the current treatment of cutaneous leishmaniasis.

PMID:34114790 | DOI:10.1021/acsinfecdis.1c00139

Phytother Res. 2021 Jun 11. doi: 10.1002/ptr.7156. Online ahead of print.

ABSTRACT

In the current study, the underlying anti-metastatic mechanism of melatonin contained in some edible plants was explored in association with transmembrane protease serine 4 (TMPRSS4) mediated metastasis and epithelial-mesenchymal transition (EMT) signaling in human HCT15 and SW620 colorectal cancer cells. Here, TMPRSS4 was highly expressed in HCT15, but was weakly expressed in SW620 cells. Melatonin exerted weak cytotoxicity, decreased invasion, adhesion, and migration, and attenuated the expression of TMPRSS4, cyclin E, pro-urokinase-type plasminogen activator (pro-uPA), p-signal transducer and activator of transcription 3 (p-STAT3), p-focal adhesion kinase (p-FAK), Snail and increased the expression of E-cadherin, p27, pp38 and p-Jun N-terminal kinases (p-JNK) in HCT15 cells. Conversely, overexpression of TMPRSS4 reduced the ability of melatonin to activate E-cadherin and reduce Snail. Furthermore, even in SW620 cells transfected with TMPRSS4-overexpression plasmid, melatonin effectively suppressed invasion and migration along with decreased expression of Snail, cyclin A, cyclin E, pro-uPA and p-FAK and increased expression of E-cadherin and p27. Overall, these findings provide evidence that melatonin suppresses metastasis in colon cancer cells via inhibition of TMPRSS4 mediated EMT.

PMID:34114707 | DOI:10.1002/ptr.7156

Chemistry. 2021 Jun 10. doi: 10.1002/chem.202101366. Online ahead of print.

ABSTRACT

We identified the gold(I)-dithiocarbamate (dtc) complex [Au(N,N-diethyl)dtc]2 as the active cytotoxic agent in the combination treatment of sodium aurothiomalate and disulfiram on a panel of cancer cell lines. In addition to demonstrating pronounced differential cytotoxicity to these cell lines, the gold complex showed no cross-resistance in therapy-surviving cancer cells. In the course of a medicinal chemistry campaign on this class of poorly soluble gold(I)-dtc complexes, we synthesized >35 derivatives and used x-ray crystallography to examine structural aspects of the dtc moiety. A group of hydroxy-substituted complexes has an improved solubility profile, and we found that these complexes form 2:1 host-guest inclusion complexes with β-cyclodextrin (CD), exhibiting a rarely observed "tail-to-tail" arrangement of the CD cones. Formulation of a hydroxy-substituted gold(I)-dtc complex with excess sulfobutylether-β-CD prevents the induction of mitochondrial reactive oxygen species, which is a major burden in the development of metallodrugs.

PMID:34114261 | DOI:10.1002/chem.202101366

Sci Rep. 2021 Jun 10;11(1):12310. doi: 10.1038/s41598-021-91625-1.

ABSTRACT

The novel SARS-CoV-2 virus emerged in December 2019 and has few effective treatments. We applied a computational drug repositioning pipeline to SARS-CoV-2 differential gene expression signatures derived from publicly available data. We utilized three independent published studies to acquire or generate lists of differentially expressed genes between control and SARS-CoV-2-infected samples. Using a rank-based pattern matching strategy based on the Kolmogorov-Smirnov Statistic, the signatures were queried against drug profiles from Connectivity Map (CMap). We validated 16 of our top predicted hits in live SARS-CoV-2 antiviral assays in either Calu-3 or 293T-ACE2 cells. Validation experiments in human cell lines showed that 11 of the 16 compounds tested to date (including clofazimine, haloperidol and others) had measurable antiviral activity against SARS-CoV-2. These initial results are encouraging as we continue to work towards a further analysis of these predicted drugs as potential therapeutics for the treatment of COVID-19.

PMID:34112877 | DOI:10.1038/s41598-021-91625-1

J Cheminform. 2021 Jun 10;13(1):44. doi: 10.1186/s13321-021-00523-1.

ABSTRACT

Target prediction is a crucial step in modern drug discovery. However, existing experimental approaches to target prediction are time-consuming and costly. Here, we introduce LigTMap, an online server with a fully automated workflow that can identify protein targets of chemical compounds among 17 classes of therapeutic proteins extracted from the PDBbind database. It combines ligand similarity search with docking and binding similarity analysis to predict putative targets. In the validation experiment of 1251 compounds, targets were successfully predicted for more than 70% of the compounds within the top-10 list. The performance of LigTMap is comparable to the current best servers SwissTargetPrediction and SEA. When testing with our newly compiled compounds from recent literature, we get improved top 10 success rate (66% ours vs. 60% SwissTargetPrediction and 64% SEA) and similar top 1 success rate (45% ours vs. 51% SwissTargetPrediction and 41% SEA). LigTMap directly provides ligand docking structures in PDB format, so that the results are ready for further structural studies in computer-aided drug design and drug repurposing projects. The LigTMap web server is freely accessible at https://cbbio.online/LigTMap . The source code is released on GitHub ( https://github.com/ShirleyWISiu/LigTMap ) under the BSD 3-Clause License to encourage re-use and further developments.

PMID:34112240 | DOI:10.1186/s13321-021-00523-1

Eur J Pharmacol. 2021 Jun 7:174233. doi: 10.1016/j.ejphar.2021.174233. Online ahead of print.

ABSTRACT

Dihydroorotate dehydrogenase (DHODH) is rate-limiting enzyme in biosynthesis of pyrimidone which catalyzes the oxidation of dihydro-orotate to orotate. Orotate is utilized in the biosynthesis of uridine-monophosphate. DHODH inhibitors have shown promise as antiviral agent against Cytomegalovirus, Ebola, Influenza, Epstein Barr and Picornavirus. Anti-SARS-CoV-2 action of DHODH inhibitors are also coming up. In this review, we have reviewed the safety and efficacy of approved DHODH inhibitors (leflunomide and teriflunomide) against COVID-19. In target-centered in silico studies, leflunomide showed favorable binding to active site of MPro and spike: ACE2 interface. In artificial-intelligence/machine-learning based studies, leflunomide was among the top 50 ligands targeting spike: ACE2 interaction. Leflunomide is also found to interact with differentially regulated pathways [identified by KEGG (Kyoto Encyclopedia of Genes and Genomes) and reactome pathway analysis of host transcriptome data] in cogena based drug-repurposing studies. Based on GSEA (gene set enrichment analysis), leflunomide was found to target pathways enriched in COVID-19. In vitro, both leflunomide (EC50 41.49±8.8μmol/L) and teriflunomide (EC50 26μmol/L) showed SARS-CoV-2 inhibition. In clinical studies, leflunomide showed significant benefit in terms of decreasing the duration of viral shredding, duration of hospital stay and severity of infection. However, no advantage was seen while combining leflunomide and IFN alpha-2a among patients with prolonged post symptomatic viral shredding. Common adverse effects of leflunomide were hyperlipidemia, leucopenia, neutropenia and liver-function alteration. Leflunomide/teriflunomide may serve as an agent of importance to achieve faster virological clearance in COVID-19, however, findings needs to be validated in bigger sized placebo controlled studies.

PMID:34111397 | DOI:10.1016/j.ejphar.2021.174233

Front Immunol. 2021 May 24;12:669400. doi: 10.3389/fimmu.2021.669400. eCollection 2021.

ABSTRACT

OBJECTIVE: Development and progression of immune-mediated inflammatory diseases (IMIDs) involve intricate dysregulation of the disease-associated genes (DAGs) and their expressing immune cells. Identifying the crucial disease-associated cells (DACs) in IMIDs has been challenging due to the underlying complex molecular mechanism.

METHODS: Using transcriptome profiles of 40 different immune cells, unsupervised machine learning, and disease-gene networks, we constructed the Disease-gene IMmune cell Expression (DIME) network and identified top DACs and DAGs of 12 phenotypically different IMIDs. We compared the DIME networks of IMIDs to identify common pathways between them. We used the common pathways and publicly available drug-gene network to identify promising drug repurposing targets.

RESULTS: We found CD4+Treg, CD4+Th1, and NK cells as top DACs in inflammatory arthritis such as ankylosing spondylitis (AS), psoriatic arthritis, and rheumatoid arthritis (RA); neutrophils, granulocytes, and BDCA1+CD14+ cells in systemic lupus erythematosus and systemic scleroderma; ILC2, CD4+Th1, CD4+Treg, and NK cells in the inflammatory bowel diseases (IBDs). We identified lymphoid cells (CD4+Th1, CD4+Treg, and NK) and their associated pathways to be important in HLA-B27 type diseases (psoriasis, AS, and IBDs) and in primary-joint-inflammation-based inflammatory arthritis (AS and RA). Based on the common cellular mechanisms, we identified lifitegrast as a potential drug repurposing candidate for Crohn's disease and other IMIDs.

CONCLUSIONS: Existing methods are inadequate in capturing the intricate involvement of the crucial genes and cell types essential to IMIDs. Our approach identified the key DACs, DAGs, common mechanisms between IMIDs, and proposed potential drug repurposing targets using the DIME network. To extend our method to other diseases, we built the DIME tool (https://bitbucket.org/systemsimmunology/dime/) to help scientists uncover the etiology of complex and rare diseases to further drug development by better-determining drug targets, thereby mitigating the risk of failure in late clinical development.

PMID:34108969 | PMC:PMC8181425 | DOI:10.3389/fimmu.2021.669400

J Biol Methods. 2021 May 26;8(2 COVID 19 Spec Iss):e148. doi: 10.14440/jbm.2021.351. eCollection 2021.

ABSTRACT

We describe a procedure of performing in silico (virtual) screening using a web-based service, the MTiOpenScreen, which is freely accessible to non-commercial users. We shall use the SARS-CoV-2 main protease as an example. Starting from a structure downloaded from the Protein Data Bank, we discuss how to prepare the coordinates file, taking into account the known biochemical background information of the target protein. The reader will find that this preparation step takes up most of the effort before the target is ready for screening. The steps for uploading the target structure and defining the search volume by critical residues, and the main parameters to use, are outlined. When this protocol is followed, the user will expect to obtain a ranked list of small approved drug compounds docked into the target structure. The results can be readily examined graphically on the web site or downloaded for studying in a local molecular graphics program such as PyMOL.

PMID:34104664 | PMC:PMC8175336 | DOI:10.14440/jbm.2021.351

medRxiv. 2021 Jun 2:2021.05.31.21254851. doi: 10.1101/2021.05.31.21254851. Preprint.

ABSTRACT

BACKGROUND: Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes and readily available compounds that reduce COVID-19 host susceptibility is a critical next step.

METHODS: We integrate COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX) and perturbargen signatures to identify candidate genes and compounds that reverse the predicted gene expression dysregulation associated with COVID-19 susceptibility. The top candidate gene is validated by testing both its GReX and observed blood transcriptome association with COVID-19 severity, as well as by in vitro perturbation to quantify effects on viral load and molecular pathway dysregulation. We validate the in silico drug repositioning analysis by examining whether the top candidate compounds decrease COVID-19 incidence based on epidemiological evidence.

RESULTS: We identify IL10RB as the top key regulator of COVID-19 host susceptibility. Predicted GReX up-regulation of IL10RB and higher IL10RB expression in COVID-19 patient blood is associated with worse COVID-19 outcomes. In vitro IL10RB overexpression is associated with increased viral load and activation of immune-related molecular pathways. Azathioprine and retinol are prioritized as candidate compounds to reduce the likelihood of testing positive for COVID-19.

CONCLUSIONS: We establish an integrative data-driven approach for gene target prioritization. We identify and validate IL10RB as a suitable molecular target for modulation of COVID-19 host susceptibility. Finally, we provide evidence for a few readily available medications that would warrant further investigation as drug repositioning candidates.

PMID:34100031 | PMC:PMC8183086 | DOI:10.1101/2021.05.31.21254851

Cell Rep Med. 2021 May 18;2(5):100281. doi: 10.1016/j.xcrm.2021.100281. eCollection 2021 May 18.

ABSTRACT

Anxiety and stress-related conditions represent a significant health burden in modern society. Unfortunately, most anxiolytic drugs are prone to side effects, limiting their long-term usage. Here, we employ a bioinformatics screen to identify drugs for repurposing as anxiolytics. Comparison of drug-induced gene-expression profiles with the hippocampal transcriptome of an importin α5 mutant mouse model with reduced anxiety identifies the hypocholesterolemic agent β-sitosterol as a promising candidate. β-sitosterol activity is validated by both intraperitoneal and oral application in mice, revealing it as the only clear anxiolytic from five closely related phytosterols. β-sitosterol injection reduces the effects of restraint stress, contextual fear memory, and c-Fos activation in the prefrontal cortex and dentate gyrus. Moreover, synergistic anxiolysis is observed when combining sub-efficacious doses of β-sitosterol with the SSRI fluoxetine. These preclinical findings support further development of β-sitosterol, either as a standalone anxiolytic or in combination with low-dose SSRIs.

PMID:34095883 | PMC:PMC8149471 | DOI:10.1016/j.xcrm.2021.100281

ACS Omega. 2021 May 19;6(21):13870-13887. doi: 10.1021/acsomega.1c01526. eCollection 2021 Jun 1.

ABSTRACT

AIM/HYPOTHESIS: The complexity and heterogeneity of multiple pathological features make Alzheimer's disease (AD) a major culprit to global health. Drug repurposing is an inexpensive and reliable approach to redirect the existing drugs for new indications. The current study aims to study the possibility of repurposing approved anticancer drugs for AD treatment. We proposed an in silico pipeline based on "omics" data mining that combines genomics, transcriptomics, and metabolomics studies. We aimed to validate the neuroprotective properties of repurposed drugs and to identify the possible mechanism of action of the proposed drugs in AD.

RESULTS: We generated a list of AD-related genes and then searched DrugBank database and Therapeutic Target Database to find anticancer drugs related to potential AD targets. Specifically, we researched the available approved anticancer drugs and excluded the information of investigational and experimental drugs. We developed a computational pipeline to prioritize the anticancer drugs having a close association with AD targets. From data mining, we generated a list of 2914 AD-related genes and obtained 49 potential druggable targets by functional enrichment analysis. The protein-protein interaction (PPI) studies for these genes revealed 641 interactions. We found that 15 AD risk/direct PPI genes were associated with 30 approved oncology drugs. The computational validation of candidate drug-target interactions, structural and functional analysis, investigation of related molecular mechanisms, and literature-based analysis resulted in four repurposing candidates, of which three drugs were epidermal growth factor receptor (EGFR) inhibitors.

CONCLUSION: Our computational drug repurposing approach proposed EGFR inhibitors as potential repurposing drugs for AD. Consequently, our proposed framework could be used for drug repurposing for different indications in an economical and efficient way.

PMID:34095679 | PMC:PMC8173619 | DOI:10.1021/acsomega.1c01526

Alzheimers Dement (N Y). 2021 May 27;7(1):e12182. doi: 10.1002/trc2.12182. eCollection 2021.

ABSTRACT

INTRODUCTION: Cilostazol may be a novel therapeutic agent for Alzheimer's disease. Its metabolite, OPC-13015, has a stronger inhibitory effect on type 3 phosphodiesterase than cilostazol.

METHODS: We prospectively enrolled patients with mild cognitive impairment to whom cilostazol was newly prescribed. Patients underwent the Montreal Cognitive Assessment (MoCA) twice, at a 6-month interval. Plasma cilostazol, OPC-13015, OPC-13213, and OPC-13217 concentrations were determined using liquid chromatography-tandem mass spectrometry.

RESULTS: MoCA score changes from baseline to the 6-month visit were positively correlated with ratios of OPC-13015 to cilostazol and total metabolites (n = 19, P = .005). Patients with higher ratios of OPC-13015 (≥0.18, median value; n = 10) had significantly higher MoCA scores (P = .036) than patients with lower ratios (the ratio <0.18, n = 9). The absolute value of OPC-13015 concentration in blood was also higher in patients with preserved cognitive function (P = .033).

DISCUSSION: Blood OPC-13015 levels may be a predictive biomarker of cilostazol treatment for Alzheimer's disease.

PMID:34095441 | PMC:PMC8158162 | DOI:10.1002/trc2.12182

Futur J Pharm Sci. 2021;7(1):113. doi: 10.1186/s43094-021-00259-7. Epub 2021 Jun 2.

ABSTRACT

BACKGROUND: Following the outbreak of the COVID-19 pandemic, there was a surge of research activity to find methods/drugs to treat it. There has been drug-repurposing research focusing on traditional medicines. Concomitantly, many researchers tried to find in silico evidence for traditional medicines. There is a great increase in article publication to commensurate the new-found research interests. This situation inspired the authors to have a comprehensive understanding of the multitude of publications related to the COVID-19 pandemic with a wish to get promising drug leads.

MAIN BODY: This review article has been conceived and made as a hybrid of the review of the selected papers advertised recently and produced in the interest of the COVID-19 situation, and in silico work done by the authors. The outcome of the present review underscores a recommendation for thorough MDS analyses of the promising drug leads. The inclusion of in silico work as an addition to the review was motivated by a recently published article of Toelzer and colleagues. The in silico investigation of free fatty acids is novel to the field and it buttresses the further MDS analysis of drug leads for managing the COVID-19 pandemic.

CONCLUSION: The review performed threw light on the need for MDS analyses to be considered together with the application of other in silico methods of prediction of pharmacologic properties directing towards the sites of drug-receptor regulation. Also, the present analysis would help formulate new recipes for complementary medicines.

PMID:34095323 | PMC:PMC8170460 | DOI:10.1186/s43094-021-00259-7

Front Oncol. 2021 May 20;11:660943. doi: 10.3389/fonc.2021.660943. eCollection 2021.

ABSTRACT

Cancer is a complex group of diseases that constitute the second largest cause of mortality worldwide. The development of new drugs for treating this disease is a long and costly process, from the discovery of the molecule through testing in phase III clinical trials, a process during which most candidate molecules fail. The use of drugs currently employed for the management of other diseases (drug repurposing) represents an alternative for developing new medical treatments. Repurposing existing drugs is, in principle, cheaper and faster than developing new drugs. Antihypertensive drugs, primarily belonging to the pharmacological categories of angiotensin-converting enzyme inhibitors, angiotensin II receptors, direct aldosterone antagonists, β-blockers and calcium channel blockers, are commonly prescribed and have well-known safety profiles. Additionally, some of these drugs have exhibited pharmacological properties useful for the treatment of cancer, rendering them candidates for drug repurposing. In this review, we examine the preclinical and clinical evidence for utilizing antihypertensive agents in the treatment of cancer.

PMID:34094953 | PMC:PMC8173186 | DOI:10.3389/fonc.2021.660943

Bioorg Chem. 2021 May 31;113:105035. doi: 10.1016/j.bioorg.2021.105035. Online ahead of print.

ABSTRACT

We managed to repurpose the old drug iodoquinol to a series of novel anticancer 7-iodo-quinoline-5,8-diones. Twelve compounds were identified as inhibitors of moderate to high potency on an inhouse MCF-7 cell line, of which 2 compounds (5 and 6) were capable of reducing NAD level in MCF-7 cells in concentrations equivalent to half of their IC50s, potentially due to NAD(P)H quinone oxidoreductase (NQO1) inhibition. The same 2 compounds (5 and 6) were capable of reducing p53 expression and increasing reactive oxygen species levels, which further supports the NQO-1 inhibitory activity. Furthermore, 4 compounds (compounds 5-7 and 10) were qualified by the Development Therapeutic Program (DTP) division of the National Cancer Institute (NCI) for full panel five-dose in vitro assay to determine their GI50 on the 60 cell lines. All five compounds showed broad spectrum sub-micromolar to single digit micromolar GI50 against a wide range of cell lines. Cell cycle analysis and dual staining assays with annexin V-FITC/propidium iodide on MCF-7 cells confirmed the capability of the most active compound (compound 5) to induce cell cycle arrest at Pre-G1 and G2/M phases as well as apoptosis. Both cell cycle arrest and apoptosis were affirmed at the molecular level by the ability of compound 5 to enhance the expression levels of caspase-3 and Bax together with suppressing that of CDK1 and Bcl-2. Additionally, an anti-angiogenic effect was evident with compound 5 as supported by the decreased expression of VEGF. Interesting binding modes within NQO-1 active site had been identified and confirmed by both molecular docking and dymanic experiments.

PMID:34091287 | DOI:10.1016/j.bioorg.2021.105035