J Appl Microbiol. 2021 Apr 22. doi: 10.1111/jam.15109. Online ahead of print.

ABSTRACT

AIM: As options to treat recalcitrant bacterial infections are increasingly limited due to multidrug-resistant strains, searching for new, effective antibacterial compounds is necessary. One strategy is to generate treatment alternatives by drug repurposing.

METHODS AND RESULTS: In this work, phenotypic microarrays were used for the screening of miscellaneous compounds against the growth and biofilm formation of Acinetobacter baumannii, an important emergent multidrug-resistant opportunistic pathogen. The results showed that the phenothiazine derivatives promethazine, trifluoperazine, thioridazine, and chlorpromazine inhibited the growth of antibiotic-sensitive and multidrug-resistant strains (showing minimal inhibitory concentrations ranging from 0·05 to 0·6 g l-1 and minimal bactericidal concentrations ranging from 0·1 to 2·5 g l-1 ). All phenothiazine derivatives were active against biofilm cells (with minimal biofilm eradication concentrations ranging from 0·5 to > 3 g l-1 ). Chlorpromazine promoted ROS production, and cell membrane and DNA damage. Chlorpromazine showed synergy with antibiotics such as ceftazidime, meropenem, and colistin, and was an effective treatment for experimentally infected Galleria mellonella when combined with ceftazidime.

CONCLUSIONS: It was demonstrated that phenothiazine derivatives, especially chlorpromazine, are drugs with attractive antibacterial properties against nosocomial MDR strains of A. baumannii, by generating ROS and cell membrane and DNA damage.

SIGNIFICANCE AND IMPACT OF STUDY: Present study indicates that repurposing phenothiazine derivatives for treating recalcitrant infections by A. baumannii could be promising.

PMID:33884726 | DOI:10.1111/jam.15109

Biomol Ther (Seoul). 2021 Apr 22. doi: 10.4062/biomolther.2021.008. Online ahead of print.

ABSTRACT

In a search for effective PPAR-γ agonists, 110 clinical drugs were screened via molecular docking, and 9 drugs, including parecoxib, were selected for subsequent biological evaluation. Molecular docking of parecoxib to the ligand-binding domain of PPAR-γ showed high binding affinity and relevant binding conformation compared with the PPAR-γ ligand/antidiabetic drug rosiglitazone. Per the docking result, parecoxib showed the best PPAR-γ transactivation in Ac2F rat liver cells. Further docking simulation and a luciferase assay suggested parecoxib would be a selective (and partial) PPAR-γ agonist. PPAR-γ activation by parecoxib induced adipocyte differentiation in 3T3-L1 murine preadipocytes. Parecoxib promoted adipogenesis in a dose-dependent manner and enhanced the expression of adipogenesis transcription factors PPAR-γ, C/EBPα, and -β. These data indicated that parecoxib might be utilized as a partial PPAR-γ agonist for drug repositioning study.

PMID:33883322 | DOI:10.4062/biomolther.2021.008

Curr Mol Pharmacol. 2021 Apr 19. doi: 10.2174/1874467214666210420115431. Online ahead of print.

ABSTRACT

BACKGROUND: Glioblastoma multiforme is one of the most heterogenous primary brain tumor with high mortality. Nevertheless, of the current therapeutic approaches, survival rate remains poor with 12 to 15 months following preliminary diagnosis, this warrants the need for effective treatment modality. Wnt/β-catenin pathway is presumably the most noteworthy pathway up-regulated in almost 80% GBM cases contributing to tumor-initiation, progression and survival. Therefore, therapeutic strategies targeting key components of Wnt/β-catenin cascade using established genotoxic agents like temozolomide and pharmacological inhibitors would be an effective approach to modulate Wnt/β-catenin pathway. Recently, drug repurposing by means of effective combination therapy has gained importance in various solid tumors including GBM, by targeting two or more proteins in a single pathway, thereby possessing the ability to overcome the hurdle implicated by chemo-resistance in GBM.

OBJECTIVE: In this context, by employing computational tools, an attempt has been carried out to speculate the novel combinations against Wnt/β-catenin signaling pathway.

METHODS: We have explored the binding interactions of three conventional drugs namely temozolomide, metformin, chloroquine along with three natural compounds viz., epigallocatechin gallate, naringenin and phloroglucinol on the major receptors of Wnt/β-catenin signaling.

RESULTS: It was noted that all the experimental compounds possessed profound interaction with the two major receptors of Wnt/β-catenin pathway.

CONCLUSION: To the best of our knowledge, this study is the first of its kind to characterize the combined interactions of the afore-mentioned drugs on Wnt/β-catenin signaling in silico and this will putatively open up new avenues for combination therapies in GBM treatment.

PMID:33881978 | DOI:10.2174/1874467214666210420115431

J Antimicrob Chemother. 2021 Apr 21:dkab072. doi: 10.1093/jac/dkab072. Online ahead of print.

ABSTRACT

BACKGROUND: Current approaches of drug repurposing against COVID-19 have not proven overwhelmingly successful and the SARS-CoV-2 pandemic continues to cause major global mortality. SARS-CoV-2 nsp12, its RNA polymerase, shares homology in the nucleotide uptake channel with the HCV orthologue enzyme NS5B. Besides, HCV enzyme NS5A has pleiotropic activities, such as RNA binding, that are shared with various SARS-CoV-2 proteins. Thus, anti-HCV NS5B and NS5A inhibitors, like sofosbuvir and daclatasvir, respectively, could be endowed with anti-SARS-CoV-2 activity.

METHODS: SARS-CoV-2-infected Vero cells, HuH-7 cells, Calu-3 cells, neural stem cells and monocytes were used to investigate the effects of daclatasvir and sofosbuvir. In silico and cell-free based assays were performed with SARS-CoV-2 RNA and nsp12 to better comprehend the mechanism of inhibition of the investigated compounds. A physiologically based pharmacokinetic model was generated to estimate daclatasvir's dose and schedule to maximize the probability of success for COVID-19.

RESULTS: Daclatasvir inhibited SARS-CoV-2 replication in Vero, HuH-7 and Calu-3 cells, with potencies of 0.8, 0.6 and 1.1 μM, respectively. Although less potent than daclatasvir, sofosbuvir alone and combined with daclatasvir inhibited replication in Calu-3 cells. Sofosbuvir and daclatasvir prevented virus-induced neuronal apoptosis and release of cytokine storm-related inflammatory mediators, respectively. Sofosbuvir inhibited RNA synthesis by chain termination and daclatasvir targeted the folding of secondary RNA structures in the SARS-CoV-2 genome. Concentrations required for partial daclatasvir in vitro activity are achieved in plasma at Cmax after administration of the approved dose to humans.

CONCLUSIONS: Daclatasvir, alone or in combination with sofosbuvir, at higher doses than used against HCV, may be further fostered as an anti-COVID-19 therapy.

PMID:33880524 | DOI:10.1093/jac/dkab072

bioRxiv. 2021 Apr 16:2021.04.15.440067. doi: 10.1101/2021.04.15.440067. Preprint.

ABSTRACT

Infection by SARS-CoV-2 generally causes mild symptoms but can lead to severe disease and death in certain populations, including the immunocompromised. Drug repurposing efforts are underway to identify compounds that interfere with SARS-CoV-2 replication or the immunopathology it can elicit. Rapamycin is among those being currently tested in clinical trials for impacts on COVID-19 severity. While rapamycin and rapamycin analogs (rapalogs) are FDA-approved for use as mTOR inhibitors in multiple clinical settings, including cancer, we previously found that rapamycin can increase the susceptibility of cells to infection by Influenza A virus. In this study, we tested the impact of rapalogs on cellular susceptibility to SARS-CoV-2 infection. We report that rapamycin and rapalogs increased SARS-CoV-2 titers in human cervical epithelial and lung epithelial cell lines to different extents, and a similar pattern of enhancement was observed using pseudovirus incorporating viral fusion proteins from SARS-CoV-2, SARS-CoV, MERS, and Influenza A Virus. Rapalogs also promoted cell entry driven by SARS-CoV-2 Spike in nasal cells and primary small airway cells, representing proximal and distal ends of the human respiratory tract, respectively. Interestingly, cell entry enhancement by the rapalog ridaforolimus was cell type-dependent, revealing a previously unrecognized functional divergence between rapalogs. The differential activity of rapalogs was associated with their capacity to induce the degradation of interferon-inducible transmembrane (IFITM) proteins, restriction factors that broadly inhibit virus infection. Our findings will spur the development of mTOR inhibitors that do not suppress the cell's first line of antiviral defense.

SIGNIFICANCE: Due to a lack of effective antivirals available to combat SARS-CoV-2 infection and the disease it causes (COVID-19), existing drugs that are clinically-approved for use in humans are being considered for deployment during this protracted pandemic. Rapamycin is an immunosuppressant that is administered to humans suffering from cancer, autoimmunity, atherosclerosis, and organ transplant rejection. While generally recognized for its inhibitory effects on the adaptive immune response, we previously showed that rapamycin can also impair intrinsic immunity, the immune system present within all cells of the body. Here, we show that rapamycin and rapamycin analogs (rapalogs) promote the first step of the SARS-CoV-2 infection cycle-entry into cells-by inducing the destruction of antiviral proteins that stand guard during virus invasion.

PMID:33880473 | PMC:PMC8057238 | DOI:10.1101/2021.04.15.440067

Res Sq. 2021 Apr 14:rs.3.rs-287183. doi: 10.21203/rs.3.rs-287183/v1. Preprint.

ABSTRACT

The current, rapidly diversifying pandemic has accelerated the need for efficient and effective identification of potential drug candidates for COVID-19. Knowledge on host-immune response to SARS-CoV-2 infection, however, remains limited with very few drugs approved to date. Viable strategies and tools are rapidly arising to address this, especially with repurposing of existing drugs offering significant promise. Here we introduce a systems biology tool, the PHENotype SIMulator, which - by leveraging available transcriptomic and proteomic databases - allows modeling of SARS-CoV-2 infection in host cells in silico to i) determine with high sensitivity and specificity (both > 96%) the viral effects on cellular host-immune response, resulting in a specific cellular SARS-CoV-2 signature and ii) utilize this specific signature to narrow down promising repurposable therapeutic strategies. Powered by this tool, coupled with domain expertise, we have identified several potential COVID-19 drugs including methylprednisolone and metformin, and further discern key cellular SARS-CoV-2-affected pathways as potential new druggable targets in COVID-19 pathogenesis.

PMID:33880466 | PMC:PMC8057245 | DOI:10.21203/rs.3.rs-287183/v1

Heliyon. 2021 Apr 15:e06841. doi: 10.1016/j.heliyon.2021.e06841. Online ahead of print.

ABSTRACT

COVID-19 has recently become one of the most challenging pandemics of the last century with deadly outcomes and a high rate of reproduction number. It emphasizes the critical need for the designing of efficient vaccines to prevent virus infection, early and fast diagnosis by the high sensitivity and selectivity diagnostic kits, and effective antiviral and protective therapeutics to decline and eliminate the viral load and side effects derived from tissue damages. Therefore, non-toxic antiviral nanoparticles (NPs) have been under development for clinical application to prevent and treat COVID-19. NPs showed great promise to provide nano vaccines against viral infections. Here, we discuss the potentials of NPs that may be applied as a drug itself or as a platform for the aim of drug and vaccine repurposing and development. Meanwhile, the advanced strategies based on NPs to detect viruses will be described with the goal of encouraging scientists to design effective and cost-benefit nanoplatforms for prevention, diagnosis, and treatment.

PMID:33880422 | PMC:PMC8049405 | DOI:10.1016/j.heliyon.2021.e06841

Adv Appl Bioinform Chem. 2021 Apr 12;14:71-85. doi: 10.2147/AABC.S304649. eCollection 2021.

ABSTRACT

INTRODUCTION: There is an urgent need to identify therapies that prevent SARS-CoV-2 infection and improve the outcome of COVID-19 patients.

OBJECTIVE: Based upon clinical observations, we proposed that some psychotropic and antihistaminic drugs could protect psychiatric patients from SARS-CoV-2 infection. This observation is investigated in the light of experimental in vitro data on SARS-CoV-2.

METHODS: SARS-CoV-2 high-throughput screening results are available at the NCATS COVID-19 portal. We investigated the in vitro anti-viral activity of many psychotropic and antihistaminic drugs using chemoinformatics approaches.

RESULTS AND DISCUSSION: We analyze our clinical observations in the light of SARS-CoV-2 experimental screening results and propose that several cationic amphiphilic psychotropic and antihistaminic drugs could protect people from SARS-CoV-2 infection; some of these molecules have very limited adverse effects and could be used as prophylactic drugs. Other cationic amphiphilic drugs used in other disease areas are also highlighted. Recent analyses of patient electronic health records reported by several research groups indicate that some of these molecules could be of interest at different stages of the disease progression. In addition, recently reported drug combination studies further suggest that it might be valuable to associate several cationic amphiphilic drugs. Taken together, these observations underline the need for clinical trials to fully evaluate the potentials of these molecules, some fitting in the so-called category of broad-spectrum antiviral agents. Repositioning orally available drugs that have moderate side effects and should act on molecular mechanisms less prone to drug resistance would indeed be of utmost importance to deal with COVID-19.

PMID:33880039 | PMC:PMC8051956 | DOI:10.2147/AABC.S304649

Medicine (Baltimore). 2021 Apr 23;100(16):e25541. doi: 10.1097/MD.0000000000025541.

ABSTRACT

Thyroid cancer is a common endocrine malignancy; however, surgery remains its primary treatment option. A novel targeted drug for the development and application of targeted therapy in thyroid cancer treatment remain underexplored.We obtained RNA sequence data of thyroid cancer from The Cancer Genome Atlas database and identified differentially expressed genes (DEGs). Then, we constructed co-expression network with DEGs and combined it with differentially methylation analysis to screen the key genes in thyroid cancer. PockDrug-Server, an online tool, was applied to predict the druggability of the key genes. Finally, we constructed protein-protein interaction (PPI) network to observe potential targeted drugs for thyroid cancer.We identified 3 genes correlated with altered DNA methylation level and oncogenesis of thyroid cancer. According to the druggable analysis and PPI network, we predicted TRAF2 and NCK-interacting protein kinase (TNIK) sever as the drug targeted for thyroid cancer. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis indicated that genes in protein-protein interaction network of TNIK enriched in mitogen-activated protein kinase signaling pathway. For drug repositioning, we identified a targeted drug of genes in PPI network.Our study provides a bioinformatics method for screening drug targets and provides a theoretical basis for thyroid cancer targeted therapy.

PMID:33879700 | DOI:10.1097/MD.0000000000025541

J Biomol Struct Dyn. 2021 Apr 21:1-17. doi: 10.1080/07391102.2021.1911851. Online ahead of print.

ABSTRACT

Candida albicans causes the fatal fungal bloodstream infection in humans called Candidiasis. Most of the Candida species are resistant to the antifungals used to treat them. Drug-resistant C. albicans poses very serious public health issues. To overcome this, the development of effective drugs with novel mechanism(s) of action is requisite. Drug repurposing is considered a viable alternative approach to overcome the above issue. In the present study, we have attempted to identify drugs that could target the essential enzyme, dihydrofolate reductase of C. albicans (CaDHFR) to find out potent and selective antifungal antifolates. FDA-approved-drug-library from the Selleck database containing 1930 drugs was screened against CaDHFR using deep-learning, molecular docking, X-score and similarity search methods. The screened compounds showing better binding with CaDHFR were subjected to molecular dynamics simulation (MDS). The results of post-MDS analysis like RMSD, RMSF, RG, SASA, the number of hydrogen bonds and PCA suggest that Paritaprevir, Lumacaftor and Rifampin can make good interaction with CaDHFR. Furthermore, analysis of binding free energy corroborated the stability of interactions as they had binding energy of -114.91 kJ mol-1, -79.22 kJ mol-1 and -78.52 kJ mol-1 for Paritaprevir, Lumacaftor and Rifampin respectively as compared to the reference (-63.10 kJ mol-1). From the results, we conclude that these drugs have great potential to inhibit CaDHFR and would add to the drug discovery against candidiasis, and hence these drugs for repurposing should be explored further.

PMID:33879017 | DOI:10.1080/07391102.2021.1911851

Int J Infect Dis. 2021 Apr 17:S1201-9712(21)00354-4. doi: 10.1016/j.ijid.2021.04.043. Online ahead of print.

ABSTRACT

OBJECTIVE: The COVID-19 pandemic has called an urgent need for drug repurposing to improve the outcome of the disease. Quaternary ammonium compounds have been demonstrated to have antiviral effects and may be of use against SARS-CoV-2 infections.

DESIGN: In this double-blind, single-center study, we enrolled patients with positive PCR test and/or CT findings for COVID-19. The participants of each group were randomly assigned to Diphenhydramine Compound (Diphenhydramine + Ammonium Chloride) plus standard of care or to Diphenhydramine alone and standard of care groups. The primary outcome was all-cause mortality within 30 days of randomization. Secondary outcomes include viral burden, clinical status, assessed by a 5-point ordinal scale, and length of stay in hospitalized patients.

RESULTS: A total of 120 patients were included in the trial, 60 of which were assigned to Ammonium Chloride group. The primary endpoint was not statistically different between the two groups (HR: 3.02 (95% CI, 0.57-16.06; p = 0.195)). Recovery time and viral burden was significantly lower in Ammonium Chloride group corresponding to odds ratios of 1.8 (95% CI, 1.15-2.83; p = 0.01) and 7.90 (95% CI, 1.62-14.17; p = 0.014), respectively.

CONCLUSION: The findings of this advocates the careful addition of Ammonium Chloride to standard of care for COVID-19 patients.

PMID:33878462 | DOI:10.1016/j.ijid.2021.04.043

Sci Rep. 2021 Apr 19;11(1):8455. doi: 10.1038/s41598-021-87976-4.

ABSTRACT

Filarial infections affect millions of individuals and are responsible for some notorious disabilities. Current treatment options involve repeated mass drug administrations, which have been met with several challenges despite some successes. Administration of doxycycline, an anti-Wolbachia agent, has shown clinical effectiveness but has several limitations, including long treatment durations and contraindications. We describe the use of an in silico drug repurposing approach to screening a library of over 3200 FDA-approved medications against the filarial endosymbiont, Wolbachia. We target the enzyme which catalyzes the first step of heme biosynthesis in the Wolbachia. This presents an opportunity to inhibit heme synthesis, which leads to depriving the filarial worm of heme, resulting in a subsequent macrofilaricidal effect. High throughput virtual screening, molecular docking and molecular simulations with binding energy calculations led to the identification of paritaprevir and nilotinib as potential anti-Wolbachia agents. Having higher binding affinities to the catalytic pocket than the natural substrate, these drugs have the structural potential to bind and engage active site residues of the wolbachia 5'-Aminolevulinic Acid Synthase. We hereby propose paritaprevir and nilotinib for experimental validations as anti-Wolbachia agents.

PMID:33875732 | DOI:10.1038/s41598-021-87976-4

Br J Clin Pharmacol. 2021 Apr 19. doi: 10.1111/bcp.14868. Online ahead of print.

ABSTRACT

AIM: Pharmacovigilance data are primarily used to identify adverse drug reactions by screening for disproportionate reporting, i.e. more reports of certain combinations of adverse events and drugs than expected. However, scanning for associations of drugs and adverse events that occur less frequently than expected provides hypotheses for drug repurposing, i.e. a known drug could be therapeutically beneficial for a new indication like the coronavirus disease (COVID-19). As coronavirus related adverse events are scarce in pharmacovigilance data prior to 2020, we searched for drugs suitable against similar viral diseases.

METHODS: In this observational, retrospective, pharmacovigilance study, drugs associated with viral respiratory tract infections and/or diseases caused by RNA-viruses, which are phylogenetically similar to SARS-CoV-2, were extracted from the U.S. FAERS pharmacovigilance data 2004Q1 to 2020Q2 using OpenVigil 2.1-MedDRA17, filtered for significant inverse associations (ROR<1 and padj <0.05), checked for implausibility (e.g., only topically) or clinical infeasibility (e.g., strong cytotoxic effects), and categorised by their WHO Anatomical Therapeutic Chemical (ATC) classification code.

RESULTS: A total of 126 drugs were identified. ATC clustering of the manually curated list of 112 candidate drugs revealed female sex hormones, anti-diabetics, neuropharmacological sigma-receptor modulators, peptidase inhibitors, antiviral drugs, nicotinic acetylcholine receptor agonists, and tyrosine kinase inhibitors as putatively antiviral.

CONCLUSION: Scanning for inverse signals in pharmacovigilance data provides new hypotheses for drug repurposing, theoretically for all indications. Concerning the treatment of viral respiratory infections, there is affirmative data for some candidate drugs; the remaining proposed candidate drugs without already known antiviral mechanism of action should stimulate further exploration.

PMID:33871897 | DOI:10.1111/bcp.14868

Clin Pharmacol Ther. 2021 May;109(5):1362. doi: 10.1002/cpt.2116. Epub 2020 Dec 13.

NO ABSTRACT

PMID:33870492 | DOI:10.1002/cpt.2116

Med Microbiol Immunol. 2021 Apr 18. doi: 10.1007/s00430-021-00707-4. Online ahead of print.

ABSTRACT

Treatment against visceral leishmaniasis (VL) is mainly hampered by drug toxicity, long treatment regimens and/or high costs. Thus, the identification of novel and low-cost antileishmanial agents is urgent. Acarbose (ACA) is a specific inhibitor of glucosidase-like proteins, which has been used for treating diabetes. In the present study, we show that this molecule also presents in vitro and in vivo specific antileishmanial activity against Leishmania infantum. Results showed an in vitro direct action against L. infantum promastigotes and amastigotes, and low toxicity to mammalian cells. In addition, in vivo experiments performed using free ACA or incorporated in a Pluronic® F127-based polymeric micelle system called ACA/Mic proved effective for the treatment of L. infantum-infected BALB/c mice. Treated animals presented significant reductions in the parasite load in their spleens, livers, bone marrows and draining lymph nodes when compared to the controls, as well as the development of antileishmanial Th1-type humoral and cellular responses based on high levels of IFN-γ, IL-12, TNF-α, GM-CSF, nitrite and IgG2a isotype antibodies. In addition, ACA or ACA-treated animals suffered from low organ toxicity. Treatment with ACA/Mic outperformed treatments using either Miltefosine or free ACA based on parasitological and immunological evaluations performed one and 15 days post-therapy. In conclusion, data suggest that the ACA/Mic is a potential therapeutic agent against L. infantum and merits further consideration for VL treatment.

PMID:33870453 | DOI:10.1007/s00430-021-00707-4

Inform Med Unlocked. 2021;23:100526. doi: 10.1016/j.imu.2021.100526. Epub 2021 Jan 24.

ABSTRACT

PROBLEM: The lately emerged SARS-CoV-2 infection, which has put the whole world in an aberrant demanding situation, has generated an urgent need for developing effective responses through artificial intelligence (AI).

AIM: This paper aims to overview the recent applications of machine learning techniques contributing to prevention, diagnosis, monitoring, and treatment of coronavirus disease (SARS-CoV-2).

METHODS: A progressive investigation of the recent publications up to November 2020, related to AI approaches towards managing the challenges of COVID-19 infection was made.

RESULTS: For patient diagnosis and screening, Convolutional Neural Network (CNN) and Support Vector Machine (SVM) are broadly applied for classification purposes. Moreover, Deep Neural Network (DNN) and homology modeling are the most used SARS-CoV-2 drug repurposing models.

CONCLUSION: While the fields of diagnosis of the SARS-CoV-2 infection by medical image processing and its dissemination pattern through machine learning have been sufficiently studied, some areas such as treatment outcome in patients and drug development need to be further investigated using AI approaches.

PMID:33869730 | PMC:PMC8044633 | DOI:10.1016/j.imu.2021.100526

Front Pharmacol. 2021 Mar 31;12:625991. doi: 10.3389/fphar.2021.625991. eCollection 2021.

ABSTRACT

Objective: The aim of the present study was repositioning of ivermectin in treatment of gastric cancer (GC) by computational prediction based on gene expression profiles of human and mouse model of GC and validations with in silico, in vitro and in vivo approaches. Methods: Computational drug repositioning was performed using connectivity map (cMap) and data/pathway mining with the Ingenuity Knowledge Base. Tissue samples of GC were collected from 16 patients and 57 mice for gene expression profiling. Additional seven independent datasets of gene expression of human GC from the TCGA database were used for validation. In silico testing was performed by constructing interaction networks of ivermectin and the downstream effects in targeted signaling pathways. In vitro testing was carried out in human GC cell lines (MKN74 and KATO-III). In vivo testing was performed in a transgenic mouse model of GC (INS-GAS mice). Results: GC gene expression "signature" and data/pathway mining but not cMAP revealed nine molecular targets of ivermectin in both human and mouse GC associated with WNT/β-catenin signaling as well as cell proliferation pathways. In silico inhibition of the targets of ivermectin and concomitant activation of ivermectin led to the inhibition of WNT/β-catenin signaling pathway in "dose-depended" manner. In vitro, ivermectin inhibited cell proliferation in time- and concentration-depended manners, and cells were arrested in the G1 phase at IC50 and shifted to S phase arrest at >IC50. In vivo, ivermectin reduced the tumor size which was associated with inactivation of WNT/β-catenin signaling and cell proliferation pathways and activation of cell death signaling pathways. Conclusion: Ivermectin could be recognized as a repositioning candidate in treatment of gastric cancer.

PMID:33867984 | PMC:PMC8044519 | DOI:10.3389/fphar.2021.625991

J Infect Public Health. 2021 Feb 9;14(5):611-619. doi: 10.1016/j.jiph.2021.01.016. Online ahead of print.

ABSTRACT

BACKGROUND: The emergence and spread of SARS-CoV-2 throughout the world has created an enormous socioeconomic impact. Although there are several promising drug candidates in clinical trials, none is available clinically. Thus, the drug repurposing approach may help to overcome the current pandemic.

METHODS: The main protease (Mpro) of SARS-CoV-2 is crucial for cleaving nascent polypeptide chains. Here, FDA-approved antiviral and anti-infection drugs were screened by high-throughput virtual screening (HTVS) followed by re-docking with standard-precision (SP) and extra-precision (XP) molecular docking. The most potent drug's binding was further validated by free energy calculations (Prime/MM-GBSA) and molecular dynamics (MD) simulation.

RESULTS: Out of 1397 potential drugs, 157 showed considerable affinity toward Mpro. After HTVS, SP, and XP molecular docking, four high-affinity lead drugs (Iodixanol, Amikacin, Troxerutin, and Rutin) with docking energies -10.629 to -11.776kcal/mol range were identified. Among them, Amikacin exhibited the lowest Prime/MM-GBSA energy (-73.800kcal/mol). It led us to evaluate other aminoglycosides (Neomycin, Paramomycin, Gentamycin, Streptomycin, and Tobramycin) against Mpro. All aminoglycosides were bound to the substrate-binding site of Mpro and interacted with crucial residues. Altogether, Amikacin was found to be the most potent inhibitor of Mpro. MD simulations of the Amikacin-Mpro complex suggested the formation of a complex stabilized by hydrogen bonds, salt bridges, and van der Waals interactions.

CONCLUSION: Aminoglycosides may serve as a scaffold to design potent drug molecules against COVID-19. However, further validation by in vitro and in vivo studies is required before using aminoglycosides as an anti-COVID-19 agent.

PMID:33866129 | DOI:10.1016/j.jiph.2021.01.016

Protein Cell. 2021 Apr 17. doi: 10.1007/s13238-021-00836-9. Online ahead of print.

ABSTRACT

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (Mpro), PLpro is responsible for processing the viral replicase polyprotein into functional units. Therefore, it is an attractive target for antiviral drug development. Here we discovered four compounds, YM155, cryptotanshinone, tanshinone I and GRL0617 that inhibit SARS-CoV-2 PLpro with IC50 values ranging from 1.39 to 5.63 μmol/L. These compounds also exhibit strong antiviral activities in cell-based assays. YM155, an anticancer drug candidate in clinical trials, has the most potent antiviral activity with an EC50 value of 170 nmol/L. In addition, we have determined the crystal structures of this enzyme and its complex with YM155, revealing a unique binding mode. YM155 simultaneously targets three "hot" spots on PLpro, including the substrate-binding pocket, the interferon stimulating gene product 15 (ISG15) binding site and zinc finger motif. Our results demonstrate the efficacy of this screening and repurposing strategy, which has led to the discovery of new drug leads with clinical potential for COVID-19 treatments.

PMID:33864621 | DOI:10.1007/s13238-021-00836-9

J Mol Model. 2021 Apr 17;27(5):128. doi: 10.1007/s00894-021-04732-1.

ABSTRACT

The COVID-19 main protease (Mpro), one of the conserved proteins of the novel coronavirus is crucial for its replication and so is a very lucrative drug target. Till now, there is no drug molecule that has been convincingly identified as the inhibitor of the function of this protein. The current pandemic situation demands a shortcut to quickly reach to a lead compound or a drug, which may not be the best but might serve as an interim solution at least. Following this notion, the present investigation uses virtual screening to find a molecule which is alraedy approved as a drug for some other disease but could be repurposed to inhibit Mpro. The potential of the present method of work to identify such a molecule, which otherwise would have been missed out, lies in the fact that instead of just using the crystallographically identified conformation of the receptor's ligand binding pocket, molecular dynamics generated ensemble of conformations has been used. It implicitly included the possibilities of "induced-fit" and/or "population shift" mechanisms of ligand fitting. As a result, the investigation has not only identified antiviral drugs like ribavirin, ritonavir, etc., but it has also captured a wide variety of drugs for various other diseases like amrubicin, cangrelor, desmopressin, diosmin, etc. as the potent possibilities. Some of these ligands are versatile to form stable interactions with various different conformations of the receptor and therefore have been statistically surfaced in the investigation. Overall the investigation offers a wide range of compounds for further testing to confirm their scopes of applications to combat the COVID-19 pandemic.

PMID:33864532 | DOI:10.1007/s00894-021-04732-1