Drug repurposing screens reveal cell-type-specific entry pathways and FDA-approved drugs active against SARS-Cov-2.
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ABSTRACT:
SUBMITTER: Dittmar M
PROVIDER: S-EPMC7985926 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The novel coronavirus (SARS-CoV-2) outbreak has started taking away the millions of lives worldwide. Identification of known and approved drugs against novel coronavirus disease (COVID-19) seems to be an urgent need for the repurposing of the existing drugs. So, here we examined a safe strategy of using approved drugs of SuperDRUG2 database against modeled membrane protein (M-protein) of SARS-CoV-2 which is essential for virus assembly by using molecular docking-based virtual screening. A total of 3639 drugs from SuperDRUG2 database and additionally 14 potential drugs reported against COVID-19 proteins were selected. Molecular docking analyses revealed that nine drugs can bind the active site of M-protein with desirable molecular interactions. We therefore applied molecular dynamics simulations and binding free energy calculation using MM-PBSA to analyze the stability of the compounds. The complexes of M-protein with the selected drugs were simulated for 50 ns and ranked according to their binding free energies. The binding mode of the drugs with M-protein was analyzed and it was observed that Colchicine, Remdesivir, Bafilomycin A1 from COVID-19 suggested drugs and Temozolomide from SuperDRUG2 database displayed desirable molecular interactions and higher binding affinity towards M-protein. Interestingly, Colchicine was found as the top most binder among tested drugs against M-protein. We therefore additionally identified four Colchicine derivatives which can bind efficiently with M-protein and have better pharmacokinetic properties. We recommend that these drugs can be tested further through in vitro studies against SARS-CoV-2 M-protein.
| S-EPMC7934671 | biostudies-literature
Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas developed from Schwann cell lineage. They account for up to 10% of all soft tissue sarcomas. Although there is an unmet need for new therapeutic agents for MPNSTs, to date there have been few transcriptomic analyses of this tumor type. We studied FDA approved drugs for MPNST treatment and compared their transcriptomic changes in cell lines before and after treatment. We demonstrated that Fludarabine treated NF1 MPNST cells exhibited altered signaling pathways such as the upregulation of the Wnt/Ca+ pathway and downregulation of the hedgehog and hypoxia signaling pathways in the Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA) analysis. The combined Colchicine and Fludarabine treatment enhanced the cytotoxicity of sporadic MPNST cells through altered signaling pathways, including increased Wnt/β-catenin pathway and others. The transcriptomic analysis comparing NF1/sporadic MPNST cells and normal Schwann cells indicated that NF1 MPNST cells had more splicing events, fewer single nucleotide variants, and induced RNA expression than sporadic MPNST cells. In summary, we identified a transcriptomic differences between MPNSTs and Schwann cells, between sporadic MPNST cells and NF1 MPNST cells, and between drug treated MPNST cells and vehicle treated cells.
2023-10-21 | GSE159896 | GEO
Project description:BackgroundThe presence of hypoxia is a poor prognostic factor in prostate cancer and the hypoxic tumor microenvironment promotes radioresistance. There is potential for drug radiotherapy combinations to improve the therapeutic ratio. We aimed to investigate whether hypoxia-associated genes could be used to identify FDA approved drugs for repurposing for the treatment of hypoxic prostate cancer.MethodsHypoxia associated genes were identified and used in the connectivity mapping software QUADrATIC to identify FDA approved drugs as candidates for repurposing. Drugs identified were tested in vitro in prostate cancer cell lines (DU145, PC3, LNCAP). Cytotoxicity was investigated using the sulforhodamine B assay and radiosensitization using a clonogenic assay in normoxia and hypoxia.ResultsMenadione and gemcitabine had similar cytotoxicity in normoxia and hypoxia in all three cell lines. In DU145 cells, the radiation sensitizer enhancement ratio (SER) of menadione was 1.02 in normoxia and 1.15 in hypoxia. The SER of gemcitabine was 1.27 in normoxia and 1.09 in hypoxia. No radiosensitization was seen in PC3 cells.ConclusionConnectivity mapping can identify FDA approved drugs for potential repurposing that are linked to a radiobiologically relevant phenotype. Gemcitabine and menadione could be further investigated as potential radiosensitizers in prostate cancer.
| S-EPMC8247203 | biostudies-literature
Project description:The current crisis of the COVID-19 pandemic around the world has been devastating as many lives have been lost to the novel SARS CoV-2 virus. Thus, there is an urgent need for the right therapeutic drug to curb the disease. However, there is time constraint in drug development, hence the need for drug repurposing approach, a relatively fast and less expensive alternative. In this study, 1,100 Food and Drug Administration (FDA) approved drugs were obtained from DrugBank and trimmed to 791 ligands based on illicitness, withdrawal from the market, being chemical agents rather than drugs, being investigational drugs and having molecular weight greater than 500 (Kg/mol). The ligands were docked against six drug targets of the novel SARS CoV-2 - 3-chymotrypsin-like protease (3CLpro), Angiotensin-converting enzyme (ACE2), ADP ribose phosphatase of NSP3 (NSP3), NSP9 RNA binding protein (NSP9), RNA dependent RNA polymerase (RdRp) and Replicase Polyprotein 1a (RP1a). UCSF Chimera, PyRx and Discovery Studio, were used to prepare the proteins, dock the ligands and visualize the complexes, respectively. Remdesivir, Lopinavir and Hydroxychloroquine were used as reference drugs. Pharmacokinetic properties of the ligands were obtained using AdmetSAR. The binding energies of the standard drugs ranged from -5.4 to -8.7 kcal/mol while over 400 of the ligands screened showed binding energy lower than -5.4 kcal/mol. Out of the 791 number of compounds docked, 10, 91, 132, 92, 54 and 96 compounds showed lower binding energies than all the controls against 3CLPro, ACE2, NSP3, NSP9, RP1a and RdRp, respectively. Ligands that bound all target proteins, and showed the lowest binding energies with good ADMET properties and particularly showed the lowest binding against ACE2 are ethynodiol diacetate (-15.6 kcal/mol), methylnaltrexone (-15.5 kcal/mol), ketazolam (-14.5 kcal/mol) and naloxone (-13.6 kcal/mol). Further investigations are recommended for ethynodiol diacetate, methylnaltrexone, ketazolam and naloxone through preclinical and clinical studies to ascertain their effectiveness.
| S-EPMC8272888 | biostudies-literature
Project description:Accumulating evidence indicates that toll-like receptor 4 (TLR4) plays a critical role in promoting adaptive immune responses and are definitively involved in the expansion and maintenance of the neuropathic pain. Though the application of docking in virtual-screening in silico methods to drug discovery has some challenge, it allows directed and meaningful design of drugs for a target protein; which can lead to low costing approaches with shortcuts; resulting in evolution and discovery of promising new drugs. Nevertheless, in parallel with virtual screening methods, attendant developments in cell culture and in-vivo studies must be achieved. In the present paper, we aimed to discover new drugs that have the ability to bind and inhibit TLR4 functions. So, after using the Pathway studio to investigate the biological pathways and protein interaction maps between TLR4 and neuropathy, we reported the application of the affinity-based approach of different pharmaceuticals; these agents contained all of the approved drugs; which could bind to Toll-like receptor 4 in blind high-throughput in silico screening. Our results demonstrated that among the primary list of 1945 retrieved compounds, 39 approved compounds could be the right candidate to perform a biological test in different in-vivo and in-vitro conditions and as a lead for further neurophysiological and neuropathological studies and treatment of neuropathic pain.
| S-EPMC6934974 | biostudies-literature
Project description:The continuing heavy toll of the COVID-19 pandemic necessitates development of therapeutic options. We adopted structure-based drug repurposing to screen FDA-approved drugs for inhibitory effects against main protease enzyme (Mpro) substrate-binding pocket of SARS-CoV-2 for non-covalent and covalent binding. Top candidates were screened against infectious SARS-CoV-2 in a cell-based viral replication assay. Promising candidates included atovaquone, mebendazole, ouabain, dronedarone, and entacapone, although atovaquone and mebendazole were the only two candidates with IC50s that fall within their therapeutic plasma concentration. Additionally, we performed Mpro assays on the top hits, which demonstrated inhibition of Mpro by dronedarone (IC50 18 µM), mebendazole (IC50 19 µM) and entacapone (IC50 9 µM). Atovaquone showed only modest Mpro inhibition, and thus we explored other potential mechanisms. Although atovaquone is Dihydroorotate dehydrogenase (DHODH) inhibitor, we did not observe inhibition of DHODH at the respective SARS-CoV-2 IC50. Metabolomic profiling of atovaquone treated cells showed dysregulation of purine metabolism pathway metabolite, where ecto-5'-nucleotidase (NT5E) was downregulated by atovaquone at concentrations equivalent to its antiviral IC50. Atovaquone and mebendazole are promising candidates with SARS-CoV-2 antiviral activity. While mebendazole does appear to target Mpro, atovaquone may inhibit SARS-CoV-2 viral replication by targeting host purine metabolism.
| S-EPMC10043961 | biostudies-literature
Project description:The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS-CoV-2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (Mpro ), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on Mpro that can be evaluated as drug targets besides the active site. Then, Food and Drug Administration (FDA)-approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. Fourteen best molecule hits for the active site of Mpro are determined. Six of these also exhibit high docking scores for the potential allosteric regions. Full-atom molecular dynamics simulations with MM-GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆Gbind ) values. ∆Gbind values reach -52.06 kcal/mol for the active site, -51.08 kcal/mol for the potential allosteric site 1, and - 42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin, and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as Mpro inhibitor candidates to be evaluated against SARS-CoV-2 infections.
| S-EPMC8441840 | biostudies-literature
Project description:There are currently no FDA-approved therapeutics available to treat Rift Valley fever virus (RVFV) infection. In an effort to repurpose drugs for RVFV treatment, a library of FDA-approved drugs was screened to determine their ability to inhibit RVFV. Several drugs from varying compound classes, including inhibitors of growth factor receptors, microtubule assembly/disassembly, and DNA synthesis, were found to reduce RVFV replication. The hepatocellular and renal cell carcinoma drug, sorafenib, was the most effective inhibitor, being non-toxic and demonstrating inhibition of RVFV in a cell-type and virus strain independent manner. Mechanism of action studies indicated that sorafenib targets at least two stages in the virus infectious cycle, RNA synthesis and viral egress. Computational modeling studies also support this conclusion. siRNA knockdown of Raf proteins indicated that non-classical targets of sorafenib are likely important for the replication of RVFV.
| S-EPMC4495339 | biostudies-literature
Project description:Glioblastoma Multiforme (GBM) tumors contain a small population of glioma stem-like cells (GSCs) among the various differentiated GBM cells (d-GCs). GSCs drive tumor recurrence, and resistance to Temozolomide (TMZ), the standard of care (SoC) for GBM chemotherapy. In order to investigate a potential link between GSC specific mitochondria function and SoC resistance, two patient-derived GSC lines were evaluated for differences in their mitochondrial metabolism. In both the lines, GSCs had significantly lower mitochondrial -content, and -function compared to d-GCs. In vitro, the standard mitochondrial-specific inhibitors oligomycin A, antimycin A, and rotenone selectively inhibited GSC proliferation to a greater extent than d-GCs and human primary astrocytes. These findings indicate that mitochondrial inhibition can be a potential GSC-targeted therapeutic strategy in GBM with minimal off-target toxicity. Mechanistically the standard mitochondrial inhibitors elicit their GSC-selective cytotoxic effects through the induction of apoptosis or autophagy pathways. We tested for GSC proliferation in the presence of 3 safe FDA-approved drugs--trifluoperazine, mitoxantrone, and pyrvinium pamoate, all of which are also known mitochondrial-targeting agents. The SoC GBM therapeutic TMZ did not trigger cytotoxicity in glioma stem cells, even at 100 μM concentration. By contrast, trifluoperazine, mitoxantrone, and pyrvinium pamoate exerted antiproliferative effects in GSCs about 30-50 fold more effectively than temozolomide. Thus, we hereby demonstrate that FDA-approved mitochondrial inhibitors induce GSC-selective cytotoxicity, and targeting mitochondrial function could present a potential therapeutic option for GBM treatment.
| S-EPMC8092590 | biostudies-literature
Project description:AimsIn December 2019, the Coronavirus disease-2019 (COVID-19) virus has emerged in Wuhan, China. In this research, the first resolved COVID-19 crystal structure (main protease) was targeted in a virtual screening study by of FDA approved drugs dataset. In addition, a knowledge gap in relations of COVID-19 with the previously known fatal Coronaviruses (CoVs) epidemics, SARS and MERS CoVs, was covered by investigation of sequence statistics and phylogenetics.Materials and methodsMolecular modeling, virtual screening, docking, sequence comparison statistics and phylogenetics of the COVID-19 main protease were investigated.Key findingsCOVID-19 Mpro formed a phylogenetic group with SARS CoV that was distant from MERS CoV. The identity% was 96.061 and 51.61 for COVID-19/SARS and COVID-19/MERS CoV sequence comparisons, respectively. The top 20 drugs in the virtual screening studies comprised a broad-spectrum antiviral (ribavirin), anti-hepatitis B virus (telbivudine), two vitamins (vitamin B12 and nicotinamide) and other miscellaneous systemically acting drugs. Of special interest, ribavirin had been used in treating cases of SARS CoV.SignificanceThe present study provided a comprehensive targeting of the first resolved COVID+19 structure of Mpro and found a suitable save drugs for repurposing against the viral Mpro. Ribavirin, telbivudine, vitamin B12 and nicotinamide can be combined and used for COVID treatment. This initiative relocates already marketed and approved safe drugs for potential use in COVID-treatment.
| S-EPMC7194560 | biostudies-literature