J Clin Endocrinol Metab. 2021 May 17:dgab343. doi: 10.1210/clinem/dgab343. Online ahead of print.

ABSTRACT

CONTEXT: Radioiodine-refractory thyroid cancers have poor outcomes and limited therapeutic options, i.e tyrosine kinase inhibitors, due to transient efficacy and toxicity of treatments. Therefore, combinatorial treatments with new therapeutic approaches are needed. Many studies link G Protein-Coupled Receptors (GPCRs) to cancer cell biology.

OBJECTIVE: To perform a specific atlas of GPCRs expression in progressive and refractory thyroid cancer to identify potential targets among GPCRs aiming at drug repositioning.

METHOD: We analyzed samples from tumor and normal thyroid tissues from 17 patients with refractory thyroid cancer (twelve papillary thyroid cancers (PTC) and five follicular thyroid cancers (FTC)). We assessed the GPCR mRNA expression using the NanoString technology with a custom panel of 371 GPCRs. The data were compared with public repositories and pharmacological databases to identify eligible drugs. The analysis of prognostic value of genes was also performed with TCGA datasets.

RESULTS: With our transcriptomic analysis, 4 receptors were found down regulated in FTC (VIPR1, ADGRL2/LPHN2, ADGRA3 and ADGRV1). In PTC, 24 receptors were deregulated, seven of which identified also by bioinformatics analyses of publicly available dataset on primary thyroid cancers (VIPR1, ADORA1, GPRC5B, P2RY8, GABBR2, CYSLTR2 and LPAR5). Among all the differentially expressed genes, 22 GPCRs are the target of approved drugs and some GPCRs were also associated with prognostic factors.

CONCLUSIONS: For the first time, we performed GPCR mRNA expression profiling in progressive and refractory thyroid cancers. These findings provide an opportunity to identify potential therapeutic targets for drug repositioning and precision medicine in radioiodine-refractory thyroid cancer.

PMID:34000025 | DOI:10.1210/clinem/dgab343

J Cell Biochem. 2021 May 17. doi: 10.1002/jcb.29954. Online ahead of print.

ABSTRACT

The emergence and spread of drug resistance in Plasmodium falciparum, the parasite causing the most severe form of human malaria, is a major threat to malaria control and elimination programs around the globe. With P. falciparum having evolved widespread resistance against a number of previously widely used drugs, currently, artemisinin (ART) and its derivatives are the cornerstones of first-line treatments of uncomplicated malaria. However, growing incidences of ART failure reflect the spread of ART-resistant P. falciparum strains. Despite current efforts to understand the primary cause of ART resistance due to mutations in the Kelch 13 gene (PfK13), the mechanism underlying ART resistance is still not completely unclear and no feasible strategies to counteract the causes and thereby restoring the efficiency of ART have been developed. We use a polypharmacology approach to identify potential drugs that can be used for the novel purpose (target). Of note, we have designed a multimodal stratagem to identify approved drugs with a potential antimalarial activity using computational drug reprofiling. Our investigations suggest that oxetacaine, simvastatin, repaglinide, aclidinium, propafenone, and lovastatin could be repurposed for malaria control and prevention.

PMID:33998049 | DOI:10.1002/jcb.29954

Contemp Clin Trials Commun. 2021 Feb 10;22:100745. doi: 10.1016/j.conctc.2021.100745. eCollection 2021 Jun.

ABSTRACT

BACKGROUND: Cryptococcosis affects more than 220,000 patients/year, with high mortality even when the standard treatment [amphotericin B (AMB), 5-flucytosin (5-FC) and fluconazole] is used. AMB presents high toxicity and 5-FC is not currently available in Brazil. In a pre-clinical study, pioglitazone (PIO - an antidiabetic drug) decreased AMB toxicity and lead to an increased mice survival, reduced morbidity and fungal burden in brain and lungs. The aim of this trial is to evaluate the efficacy and safety of PIO combined with standard antifungal treatment for human cryptococcosis.

METHODS: A phase 1/2, randomized, double blind, placebo-controlled trial will be performed with patients from Belo Horizonte, Brazil. They will be divided into three groups (placebo, PIO 15 mg/day or PIO 45 mg/day) and will receive an additional pill during the induction phase of cryptococcosis' treatment. Our hypothesis is that treated patients will have increased survival, so the primary outcome will be the mortality rate. Patients will be monitored for survival, side effects, fungal burden and inflammatory mediators in blood and cerebrospinal fluid. The follow up will occur for up 60 days.

CONCLUSIONS: We expect that PIO will be an adequate adjuvant to the standard cryptococcosis' treatment.

TRIAL REGISTRATION: ICTRP/WHO (and International Clinical Trial Registry Plataform (ICTRP/WHO) (http://apps.who.int/trialsearch/Trial2.aspx?TrialID=RBR-9fv3f4), RBR-9fv3f4 (http://www.ensaiosclinicos.gov.br/rg/RBR-9fv3f4). UTN Number: U1111-1226-1535. Ethical approvement number: CAAE 17377019.0.0000.5149.

PMID:33997457 | PMC:PMC8099743 | DOI:10.1016/j.conctc.2021.100745

Front Oncol. 2021 Apr 29;11:670804. doi: 10.3389/fonc.2021.670804. eCollection 2021.

ABSTRACT

Drug repositioning is a strategy for identifying new antitumor drugs; this strategy allows existing and approved clinical drugs to be innovatively repurposed to treat tumors. Based on the similarities between parasitic diseases and cancer, recent studies aimed to investigate the efficacy of existing antiparasitic drugs in cancer. In this review, we selected two antihelminthic drugs (macrolides and benzimidazoles) and two antiprotozoal drugs (artemisinin and its derivatives, and quinolines) and summarized the research progresses made to date on the role of these drugs in cancer. Overall, these drugs regulate tumor growth via multiple targets, pathways, and modes of action. These antiparasitic drugs are good candidates for comprehensive, in-depth analyses of tumor occurrence and development. In-depth studies may improve the current tumor diagnoses and treatment regimens. However, for clinical application, current investigations are still insufficient, warranting more comprehensive analyses.

PMID:33996598 | PMC:PMC8117216 | DOI:10.3389/fonc.2021.670804

Front Immunol. 2021 Apr 28;12:659943. doi: 10.3389/fimmu.2021.659943. eCollection 2021.

ABSTRACT

Advancement in the understanding of inflammation regulation during tuberculosis (TB) treatment has led to novel therapeutic approaches being proposed. The use of immune mediators like anti-inflammatory and pro-resolving molecules for such, merits attention. Drug repurposing is a widely used strategy that seeks to identify new targets to treat or manage diseases. The widely explored nonsteroidal anti-inflammatory drug (NSAID) ibuprofen and a more recently explored pharmaconutrition therapy using omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs), have the potential to modulate the immune system and are thus considered potential repurposed drugs in this context. These approaches may be beneficial as supportive therapy to the already existing treatment regimen to improve clinical outcomes. Here, we applied adjunct ibuprofen and n-3 LCPUFA therapy, respectively, with standard anti-TB treatment, in a C3HeB/FeJ murine model of TB. Bacterial loads, lung pathology, lung cytokines/chemokines and lung lipid mediators were measured as outcomes. Lung bacterial load on day 14 post-treatment (PT) was lower in the n-3 LCPUFA, compared to the ibuprofen group (p = 0.039), but was higher in the ibuprofen group than the treated control group (p = 0.0315). Treated control and ibuprofen groups had more free alveolar space initially as compared to the n-3 LCPUFA group (4 days PT, p= 0.0114 and p= 0.002, respectively); however, significantly more alveolar space was present in the n-3 LCPUFA group as compared to the ibuprofen group by end of treatment (14 days PT, p = 0.035). Interleukin 6 (IL-6) was lower in the ibuprofen group as compared to the treated control, EPA/DHA and untreated control groups at 4 days PT (p = 0.019, p = 0.019 and p = 0.002, respectively). Importantly, pro-resolving EPA derived 9-HEPE, 11-HEPE, 12-HEPE and 18-HEPE lipid mediators (LMs) were significantly higher in the EPA/DHA group as compared to the ibuprofen and treated control groups. This suggests that n-3 LCPUFAs do improve pro-resolving and anti-inflammatory properties in TB, and it may be safe and effective to co-administer as adjunct therapy with standard TB treatment, particularly longer-term. Also, our results show host benefits upon short-term co-administration of ibuprofen, but not throughout the entire TB treatment course.

PMID:33995381 | PMC:PMC8113969 | DOI:10.3389/fimmu.2021.659943

Front Physiol. 2021 Apr 27;12:652799. doi: 10.3389/fphys.2021.652799. eCollection 2021.

ABSTRACT

The pestilential pathogen SARS-CoV-2 has led to a seemingly ceaseless pandemic of COVID-19. The healthcare sector is under a tremendous burden, thus necessitating the prognosis of COVID-19 severity. This in-depth study of plasma proteome alteration provides insights into the host physiological response towards the infection and also reveals the potential prognostic markers of the disease. Using label-free quantitative proteomics, we performed deep plasma proteome analysis in a cohort of 71 patients (20 COVID-19 negative, 18 COVID-19 non-severe, and 33 severe) to understand the disease dynamics. Of the 1200 proteins detected in the patient plasma, 38 proteins were identified to be differentially expressed between non-severe and severe groups. The altered plasma proteome revealed significant dysregulation in the pathways related to peptidase activity, regulated exocytosis, blood coagulation, complement activation, leukocyte activation involved in immune response, and response to glucocorticoid biological processes in severe cases of SARS-CoV-2 infection. Furthermore, we employed supervised machine learning (ML) approaches using a linear support vector machine model to identify the classifiers of patients with non-severe and severe COVID-19. The model used a selected panel of 20 proteins and classified the samples based on the severity with a classification accuracy of 0.84. Putative biomarkers such as angiotensinogen and SERPING1 and ML-derived classifiers including the apolipoprotein B, SERPINA3, and fibrinogen gamma chain were validated by targeted mass spectrometry-based multiple reaction monitoring (MRM) assays. We also employed an in silico screening approach against the identified target proteins for the therapeutic management of COVID-19. We shortlisted two FDA-approved drugs, namely, selinexor and ponatinib, which showed the potential of being repurposed for COVID-19 therapeutics. Overall, this is the first most comprehensive plasma proteome investigation of COVID-19 patients from the Indian population, and provides a set of potential biomarkers for the disease severity progression and targets for therapeutic interventions.

PMID:33995121 | PMC:PMC8120435 | DOI:10.3389/fphys.2021.652799

Front Pharmacol. 2021 Apr 29;12:664176. doi: 10.3389/fphar.2021.664176. eCollection 2021.

ABSTRACT

7-Ethyl-10-hydroxycamptothecin (SN-38) is an active metabolite of CPT-11, which can inhibit DNA topoisomerase I, DNA synthesis and cause frequent DNA single-strand breaks. In our study, SN-38 was characterized as a potent and reversible BRD4 inhibitor [IC50 = 660.2 nM against BRD4 (BD1) and IC50 = 547.7 nM against BRD4 (BD2)] in biochemical assay using drug repurposing strategy. Additional cellular assay suggested that SN-38 can bind BRD4 in human leukemic cell K562 and inhibit cell growth with IC50 = 0.2798 μM in a BRD4 dependent manner partially. Additionally, mechanism study indicated that SN-38 can induce the accumulation of BRD4 substrate c-Myc and cleavage of caspase 3. In sum, our findings identified BRD4 as a new target of SN-38 and reveals SN-38 as a modifier of histone acetylation reader for the first time, which may provide a new insight for further optimization of dual target inhibitor.

PMID:33995089 | PMC:PMC8117000 | DOI:10.3389/fphar.2021.664176

Front Neurosci. 2021 Apr 30;15:657714. doi: 10.3389/fnins.2021.657714. eCollection 2021.

ABSTRACT

Repurposing ketamine in the therapy of depression could well represent a breakthrough in understanding the etiology of depression. Ketamine was originally used as an anesthetic drug and later its use was extended to other therapeutic applications such as analgesia and the treatment of addiction. At the same time, the abuse of ketamine as a recreational drug has generated a concern for its psychotropic and potential long-term effects; nevertheless, its use as a fast acting antidepressant in treatment-resistant patients has boosted the interest in the mechanism of action both in psychiatry and in the wider area of neuroscience. This article provides a comprehensive overview of the actions of ketamine and intends to cover: (i) the evaluation of its clinical use in the treatment of depression and suicidal behavior; (ii) the potential use of ketamine in pediatrics; (iii) a description of its mechanism of action; (iv) the involvement of specific brain areas in producing antidepressant effects; (v) the potential interaction of ketamine with the hypothalamic-pituitary-adrenal axis; (vi) the effect of ketamine on neuronal transmission in the bed nucleus of stria terminalis and on its output; (vii) the evaluation of any gender-dependent effects of ketamine; (viii) the interaction of ketamine with the inflammatory processes involved in depression; (ix) the evaluation of the effects observed with single or repeated administration; (x) a description of any adverse or cognitive effects and its abuse potential. Finally, this review attempts to assess whether ketamine's use in depression can improve our knowledge of the etiopathology of depression and whether its therapeutic effect can be considered an actual cure for depression rather than a therapy merely aimed to control the symptoms of depression.

PMID:33994933 | PMC:PMC8120160 | DOI:10.3389/fnins.2021.657714

Brief Bioinform. 2021 May 17:bbab113. doi: 10.1093/bib/bbab113. Online ahead of print.

ABSTRACT

To attain promising pharmacotherapies, researchers have applied drug repurposing (DR) techniques to discover the candidate medicines to combat the coronavirus disease 2019 (COVID-19) outbreak. Although many DR approaches have been introduced for treating different diseases, only structure-based DR (SBDR) methods can be employed as the first therapeutic option against the COVID-19 pandemic because they rely on the rudimentary information about the diseases such as the sequence of the severe acute respiratory syndrome coronavirus 2 genome. Hence, to try out new treatments for the disease, the first attempts have been made based on the SBDR methods which seem to be among the proper choices for discovering the potential medications against the emerging and re-emerging infectious diseases. Given the importance of SBDR approaches, in the present review, well-known SBDR methods are summarized, and their merits are investigated. Then, the databases and software applications, utilized for repurposing the drugs against COVID-19, are introduced. Besides, the identified drugs are categorized based on their targets. Finally, a comparison is made between the SBDR approaches and other DR methods, and some possible future directions are proposed.

PMID:33993214 | DOI:10.1093/bib/bbab113

J Clin Neurosci. 2021 Jun;88:163-172. doi: 10.1016/j.jocn.2021.03.010. Epub 2021 Mar 19.

ABSTRACT

The current 2019 novel coronavirus disease (COVID-19), an emerging infectious disease, is undoubtedly the most challenging pandemic in the 21st century. A total of 92,977,768 confirmed cases of COVID-19 and 1,991,289 deaths were reported globally up to January 14, 2021. COVID-19 also affects people's mental health and quality of life. At present, there is no effective therapeutic strategy for the management of this disease. Therefore, in the absence of a specific vaccine or curative treatment, it is an urgent need to identify safe, effective and globally available drugs for reducing COVID-19 morbidity and fatalities. In this review, we focus on selective serotonin reuptake inhibitors (SSRIs: a class of antidepressant drugs with widespread availability and an optimal tolerability profile) that can potentially be repurposed for COVID-19 and are currently being tested in clinical trials. We also summarize the existing literature on what is known about the link between serotonin (5-HT) and the immune system. From the evidence reviewed here, we propose fluoxetine as an adjuvant therapeutic agent for COVID-19 based on its known immunomodulatory, anti-inflammatory and antiviral properties. Fluoxetine may potentially reduce pro-inflammatory chemokine/cytokines levels (such as CCL-2, IL-6, and TNF-α) in COVID-19 patients. Furthermore, fluoxetine may help to attenuate neurological complications of COVID-19.

PMID:33992179 | DOI:10.1016/j.jocn.2021.03.010

Med Chem. 2021 May 10. doi: 10.2174/1573406417666210511001241. Online ahead of print.

ABSTRACT

BACKGROUND: The progression of ovarian cancer seems to be related to HDAC1, HDAC3 and HDAC6 activity. A possible strategy for improving therapies for treating ovarian carcinoma, minimizing the preclinical screenings, is the repurposing of already approved pharmaceutical products as inhibitors of these enzymes.

OBJECTIVE: This work was aimed to implement a computational strategy for identifying new HDAC inhibitors for ovarian carcinoma treatment among approved drugs.

METHOD: The CHEMBL database was used to construct training, test and decoys sets for performing and validating HDAC1, HDAC3 and HDAC6 3D-QSAR models obtained by using FLAP program. Docking and MD simulations were used in combination with the generated models to identify novel potential HDAC inhibitors. Cell viability assays and Western blot analyses were performed on normal and cancer cells for a direct evaluation of the anti-proliferative activity and an in vitro estimation of HDAC inhibition of the compounds selected through in silico screening.

RESULT: The best quantitative prediction was obtained for the HDAC6 3D-QSAR model. The screening of approved drugs highlighted a new potential use as HDAC inhibitors for some compounds, in particular nitrofuran derivatives, usually known for their antibacterial activity, and frequently used as antimicrobial adjuvant therapy in cancer treatment. Experimental evaluation of these derivatives highlighted a significant antiproliferative activity against cancer cell lines overexpressing HDAC6, and an increase in acetylated alpha-tubulin levels.

CONCLUSION: Experimental results support the hypothesis of a potential direct interaction of nitrofuran derivatives with HDACs. In addition to the possible repurposing of already approved drugs, this work suggests the nitro group as a new zinc binding group, able to interact with the catalytic zinc ion of HDACs.

PMID:33992059 | DOI:10.2174/1573406417666210511001241

Neurotherapeutics. 2021 May 13. doi: 10.1007/s13311-021-01064-z. Online ahead of print.

ABSTRACT

The continuous adherence to the conventional "one target, one drug" paradigm has failed so far to provide effective therapeutic solutions for heterogeneous and multifactorial diseases as amyotrophic lateral sclerosis (ALS), a rare progressive and chronic, debilitating neurological disease for which no cure is available. The present study is aimed at finding innovative solutions and paradigms for therapy in ALS pathogenesis, by exploiting new insights from Network Medicine and drug repurposing strategies. To identify new drug-ALS disease associations, we exploited SAveRUNNER, a recently developed network-based algorithm for drug repurposing, which quantifies the proximity of disease-associated genes to drug targets in the human interactome. We prioritized 403 SAveRUNNER-predicted drugs according to decreasing values of network similarity with ALS. Among catecholamine, dopamine, serotonin, histamine, and GABA receptor modulators, as well as angiotensin-converting enzymes, cyclooxygenase isozymes, and serotonin transporter inhibitors, we found some interesting no customary ALS drugs, including amoxapine, clomipramine, mianserin, and modafinil. Furthermore, we strengthened the SAveRUNNER predictions by a gene set enrichment analysis that confirmed modafinil as a drug with the highest score among the 121 identified drugs with a score > 0. Our results contribute to gathering further proofs of innovative solutions for therapy in ALS pathogenesis.

PMID:33987813 | DOI:10.1007/s13311-021-01064-z

PeerJ Comput Sci. 2021 May 3;7:e506. doi: 10.7717/peerj-cs.506. eCollection 2021.

ABSTRACT

Semi-supervised learning combines supervised and unsupervised learning approaches to learn predictive models from both labeled and unlabeled data. It is most appropriate for problems where labeled examples are difficult to obtain but unlabeled examples are readily available (e.g., drug repurposing). Semi-supervised predictive clustering trees (SSL-PCTs) are a prominent method for semi-supervised learning that achieves good performance on various predictive modeling tasks, including structured output prediction tasks. The main issue, however, is that the learning time scales quadratically with the number of features. In contrast to axis-parallel trees, which only use individual features to split the data, oblique predictive clustering trees (SPYCTs) use linear combinations of features. This makes the splits more flexible and expressive and often leads to better predictive performance. With a carefully designed criterion function, we can use efficient optimization techniques to learn oblique splits. In this paper, we propose semi-supervised oblique predictive clustering trees (SSL-SPYCTs). We adjust the split learning to take unlabeled examples into account while remaining efficient. The main advantage over SSL-PCTs is that the proposed method scales linearly with the number of features. The experimental evaluation confirms the theoretical computational advantage and shows that SSL-SPYCTs often outperform SSL-PCTs and supervised PCTs both in single-tree setting and ensemble settings. We also show that SSL-SPYCTs are better at producing meaningful feature importance scores than supervised SPYCTs when the amount of labeled data is limited.

PMID:33987461 | PMC:PMC8101547 | DOI:10.7717/peerj-cs.506

Front Chem. 2021 Apr 27;9:607139. doi: 10.3389/fchem.2021.607139. eCollection 2021.

ABSTRACT

Leishmaniasis is a group of neglected infectious diseases, with approximately 1. 3 million new cases each year, for which the available therapies have serious limitations. Therefore, it is extremely important to apply efficient and low-cost methods capable of selecting the best therapeutic targets to speed up the development of new therapies against those diseases. Thus, we propose the use of integrated computational methods capable of evaluating the druggability of the predicted proteomes of Leishmania braziliensis and Leishmania infantum, species responsible for the different clinical manifestations of leishmaniasis in Brazil. The protein members of those proteomes were assessed based on their structural, chemical, and functional contexts applying methods that integrate data on molecular function, biological processes, subcellular localization, drug binding sites, druggability, and gene expression. These data were compared to those extracted from already known drug targets (BindingDB targets), which made it possible to evaluate Leishmania proteomes for their biological relevance and treatability. Through this methodology, we identified more than 100 proteins of each Leishmania species with druggability characteristics, and potential interaction with available drugs. Among those, 31 and 37 proteins of L. braziliensis and L. infantum, respectively, have never been tested as drug targets, and they have shown evidence of gene expression in the evolutionary stage of pharmacological interest. Also, some of those Leishmania targets showed an alignment similarity of <50% when compared to the human proteome, making these proteins pharmacologically attractive, as they present a reduced risk of side effects. The methodology used in this study also allowed the evaluation of opportunities for the repurposing of compounds as anti-leishmaniasis drugs, inferring potential interaction between Leishmania proteins and ~1,000 compounds, of which only 15 have already been tested as a treatment for leishmaniasis. Besides, a list of potential Leishmania targets to be tested using drugs described at BindingDB, such as the potential interaction of the DEAD box RNA helicase, TRYR, and PEPCK proteins with the Staurosporine compound, was made available to the public.

PMID:33987166 | PMC:PMC8111926 | DOI:10.3389/fchem.2021.607139

PeerJ. 2021 Apr 30;9:e11360. doi: 10.7717/peerj.11360. eCollection 2021.

ABSTRACT

Mycophenolate mofetil is an established anti-proliferative and immune-suppressive agent that minimizes the proliferation of inflammatory cells by interfering with nucleic acid synthesis. Herein, we report our discovery of the prostaglandin inhibiting properties of MMF, which offers new applications for the drug in the treatment of inflammatory diseases. The estimated values of IC50MMFCOX-1, IC50MMFCOX-2, and IC50MMF5-LOX were 5.53, 0.19, and 4.47 µM, respectively. In contrast, mycophenolic acid (MPA) showed slightly stronger inhibition: IC50MPACOX-1, IC50MPACOX-2, and IC50MPA5-LOX were 4.62, 0.14, and 4.49 µM, respectively. These results indicate that MMF and MPA are, respectively, 28.6 and 33 times more selective for cyclooxygenase-2 than for cyclooxygenase-1, which implies that MMF would have less impact on the gastric mucosa than most nonselective, nonsteroidal anti-inflammatory drugs. Furthermore, MMF provided dose-dependent relief of acute inflammation in the carrageenan-induced rat paw edema test, with results comparable to those of celecoxib and indomethacin. Molecular dynamics simulations indicated that the MMF bond with COX-2 was stable, as evidenced by a low root-mean-square deviation of atomic positions, complementary per-residue root-mean-square fluctuation, and 0-4 hydrogen bonds during the 50-ns simulation time. Therefore, MMF provides immune-suppressing, cyclooxygenase-inhibiting, and inflammation-relieving properties. Our results indicate that MMF can be 1) repositioned for inflammation treatment without the need for further expensive clinical trials, 2) used for local acute inflammations, and 3) used as a sparing agent for other steroid and non-steroid anti-inflammatory medications, especially in topical applications.

PMID:33987026 | PMC:PMC8092108 | DOI:10.7717/peerj.11360

Sci Rep. 2021 May 13;11(1):10169. doi: 10.1038/s41598-021-89627-0.

ABSTRACT

Sirtuin 2 (Sirt2) nicotinamide adenine dinucleotide-dependent deacetylase enzyme has been reported to alter diverse biological functions in the cells and onset of diseases, including cancer, aging, and neurodegenerative diseases, which implicate the regulation of Sirt2 function as a potential drug target. Available Sirt2 inhibitors or modulators exhibit insufficient specificity and potency, and even partially contradictory Sirt2 effects were described for the available inhibitors. Herein, we applied computational screening and evaluation of FDA-approved drugs for highly selective modulation of Sirt2 activity via a unique inhibitory mechanism as reported earlier for SirReal2 inhibitor. Application of stringent molecular docking results in the identification of 48 FDA-approved drugs as selective putative inhibitors of Sirt2, but only top 10 drugs with docking scores > - 11 kcal/mol were considered in reference to SirReal2 inhibitor for computational analysis. The molecular dynamics simulations and post-simulation analysis of Sirt2-drug complexes revealed substantial stability for Fluphenazine and Nintedanib with Sirt2. Additionally, developed 3D-QSAR-models also support the inhibitory potential of drugs, which exclusively revealed highest activities for Nintedanib (pIC50 ≥ 5.90 µM). Conclusively, screened FDA-approved drugs were advocated as promising agents for Sirt2 inhibition and required in vitro investigation for Sirt2 targeted drug development.

PMID:33986372 | DOI:10.1038/s41598-021-89627-0

PLoS One. 2021 May 13;16(5):e0251801. doi: 10.1371/journal.pone.0251801. eCollection 2021.

ABSTRACT

Drug repurposing studies targeting inhibition of RNA dependent RNA polymerase (RdRP) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) have exhibited the potential effect of small molecules. In the present work a detailed interaction study between the phytochemicals from Indian medicinal plants and the RdRP of SARS-CoV-2 has been performed. The top four phytochemicals obtained through molecular docking were, swertiapuniside, cordifolide A, sitoindoside IX, and amarogentin belonging to Swertia chirayita, Tinospora cordifolia and Withania somnifera. These ligands bound to the RdRP were further studied using molecular dynamics simulations. The principal component analysis of these systems showed significant conformational changes in the finger and thumb subdomain of the RdRP. Hydrogen bonding, salt-bridge and water mediated interactions supported by MM-GBSA free energy of binding revealed strong binding of cordifolide A and sitoindoside IX to RdRP. The ligand-interacting residues belonged to either of the seven conserved motifs of the RdRP. These residues were polar and charged amino acids, namely, ARG 553, ARG 555, ASP 618, ASP 760, ASP 761, GLU 811, and SER 814. The glycosidic moieties of the phytochemicals were observed to form favourable interactions with these residues. Hence, these phytochemicals may hold the potential to act as RdRP inhibitors owing to their stability in binding to the druggable site.

PMID:33984041 | DOI:10.1371/journal.pone.0251801

Sci Rep. 2021 May 12;11(1):10136. doi: 10.1038/s41598-021-89171-x.

ABSTRACT

Pathogenic mosquito-borne viruses are a serious public health issue in tropical and subtropical regions and are increasingly becoming a problem in other climate zones. Drug repositioning is a rapid, pharmaco-economic approach that can be used to identify compounds that target these neglected tropical diseases. We have applied a computational drug repositioning method to five mosquito-borne viral infections: dengue virus (DENV), zika virus (ZIKV), West Nile virus (WNV), Japanese encephalitis virus (JEV) and Chikungunya virus (CHIV). We identified signature molecules and pathways for each virus infection based on omics analyses, and determined 77 drug candidates and 146 proteins for those diseases by using a filtering method. Based on the omics analyses, we analyzed the relationship among drugs, target proteins and the five viruses by projecting the signature molecules onto a human protein-protein interaction network. We have classified the drug candidates according to the degree of target proteins in the protein-protein interaction network for the five infectious diseases.

PMID:33980888 | DOI:10.1038/s41598-021-89171-x

Drug Metab Rev. 2021 May 12:1-83. doi: 10.1080/03602532.2021.1928686. Online ahead of print.

ABSTRACT

Developing effective strategies to confront coronavirus disease 2019 (COVID-19) has become one of the greatest concerns of the scientific community. In addition to the vast number of global mortalities due to COVID-19, since its outbreak, almost every aspect of human lives has changed one way or another. In the present review, various defensive and offensive strategies developed to confront COVID-19 are illustrated. The Administration of immune-boosting micronutrients/agents, as well as the inhibition of the activity of incompetent gatekeepers, including some host cell receptors (e.g. ACE2) and proteases (e.g. TMPRSS2), are some efficient defensive strategies. Antibody/phage therapies and specifically vaccines also play a prominent role in the enhancement of host defense against COVID-19. Nanotechnology, however, can considerably weaken the virulence of SARS-CoV-2, utilizing fake cellular locks (compounds mimicking cell receptors) to block the viral keys (spike proteins). Generally, two strategies are developed to interfere with the binding of spike proteins to the host cell receptors, either utilizing fake cellular locks to block the viral keys or utilizing fake viral keys to block the cellular locks. Due to their evolutionary conserved nature, viral enzymes, including 3CLpro, PLpro, RdRp, and helicase are highly potential targets for drug repurposing strategy. Thus, various steps of viral replication/transcription can effectively be blocked by their inhibition, leading to the elimination of SARS-CoV-2. Moreover, RNA decoy and CRISPR technologies likely offer the best offensive strategies after viral entry into the host cells, inhibiting the viral replication/assembly in the infected cells and substantially reducing the quantity of viral progeny.

PMID:33980089 | DOI:10.1080/03602532.2021.1928686

Basic Clin Pharmacol Toxicol. 2021 May 11. doi: 10.1111/bcpt.13600. Online ahead of print.

ABSTRACT

BACKGROUND: The COVID-19 pandemic has demanded effective therapeutic protocol from researchers and clinicians across the world. Currently, a large amount of primary data have been generated from several preclinical studies. At least 300 clinical trials are underway for drug repurposing against COVID-19; the clinician needs objective evidence-based medication to treat COVID-19.

OBSERVATIONS: Single-stranded RNA viral genome of SARS-CoV-2 encodes structural proteins (spike protein), non-structural enzymatic proteins (RNA-dependent RNA polymerase, helicase, papain-like protease, 3-chymotrypsin-like protease), and other accessory proteins. These four enzymatic proteins on spike protein are rate-limiting steps in viral replications and, therefore, an attractive target for drug development against SARS-CoV-2. In silico and in vitro studies have identified various potential epitomes as candidate sequences for vaccine development. These studies have also revealed potential targets for drug development and drug repurposing against COVID-19. Clinical trials utilizing antiviral drugs and other drugs have given inconclusive results regarding their clinical efficacy and side effects. The need of angiotensin-converting enzyme (ACE-2) inhibitors/angiotensin receptor blockers and corticosteroids has been recommended. Western countries have adopted telemedicine as an alternative to prevent transmission of infection in the population. Currently, no proven, evidence-based therapeutic regimen exists for COVID-19.

CONCLUSION: The COVID-19 pandemic has put tremendous pressure on researchers to evaluate and approve drugs effective against the disease. Well-controlled randomized trials should assess medicines that are not marketed with substantial evidence of safety and efficacy and more emphasis on time tested approaches for drug evaluation.

PMID:33977663 | DOI:10.1111/bcpt.13600