Mol Cells. 2021 Sep 14. doi: 10.14348/molcells.2021.076. Online ahead of print.

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has become a global health concern. Various SARS-CoV-2 vaccines have been developed and are being used for vaccination worldwide. However, no therapeutic agents against coronavirus disease 2019 (COVID-19) have been developed so far; therefore, new therapeutic agents are urgently needed. In the present study, we evaluated several hepatitis C virus direct-acting antivirals as potential candidates for drug repurposing against COVID-19. Theses include asunaprevir (a protease inhibitor), daclatasvir (an NS5A inhibitor), and sofosbuvir (an RNA polymerase inhibitor). We found that asunaprevir, but not sofosbuvir and daclatasvir, markedly inhibited SARS-CoV-2-induced cytopathic effects in Vero E6 cells. Both RNA and protein levels of SARS-CoV-2 were significantly decreased by treatment with asunaprevir. Moreover, asunaprevir profoundly decreased virion release from SARS-CoV-2-infected cells. A pseudoparticle entry assay revealed that asunaprevir blocked SARS-CoV-2 infection at the binding step of the viral life cycle. Furthermore, asunaprevir inhibited SARS-CoV-2 propagation in human lung Calu-3 cells. Collectively, we found that asunaprevir displays broad-spectrum antiviral activity and therefore might be worth developing as a new drug repurposing candidate for COVID-19.

PMID:34518443 | DOI:10.14348/molcells.2021.076

Clin Dermatol. 2021 May-Jun;39(3):430-445. doi: 10.1016/j.clindermatol.2021.01.020. Epub 2021 Feb 2.

ABSTRACT

No pharmaceutical products have been demonstrated to be safe and effective to specifically treat coronavirus disease 2019 (COVID-19); therefore, the therapy administered to infected patients remains symptomatic and empiric. Alongside the development of new, often high-cost drugs, a different tactic is being applied in parallel, investigating long-established, inexpensive medications originally designed for a variety of diseases to study their potential in treating COVID-19. The skin is the largest organ of the human body. With more than 3,000 skin conditions identified, the specialty of dermatology offers a rich armamentarium of systemic therapeutic agents aimed to treat the various chronic immunologically mediated, metabolic, infectious, occupational, inherited, or paraneoplastic dermatoses. Dermatologists have extensive experience with many drugs that have demonstrated promising in vitro antiviral action (directly targeting the viral replication). Many of these drugs have been used as nonspecific immunosuppressive strategies, such as glucocorticoids, synthetic antimalarials, colchicine, or other immunomodulators, and a number of targeted therapeutics have been directed at controlling hyperinflammatory processes similar to the "cytokine storm" associated with COVID-19 infection. We discuss several dermatologic drugs that have already been used or may have a promising role in the treatment of COVID-19.

PMID:34518001 | DOI:10.1016/j.clindermatol.2021.01.020

Math Biosci Eng. 2021 Jul 21;18(5):6328-6385. doi: 10.3934/mbe.2021316.

ABSTRACT

Breast cancer is one of the most common cancers and generally affects women. It is a heterogeneous disease that presents different entities, different biological characteristics, and differentiated clinical behaviors. With this in mind, this literature review had as its main objective to analyze the path taken from the simple use of classical drugs to the application of mathematical models, which through the many ongoing studies, have been considered as one of the reliable strategies, explaining the reasons why chemotherapy is not always successful. Besides, the most commonly mentioned strategies are immunotherapy, which includes techniques and therapies such as the use of antibodies, cytokines, antitumor vaccines, oncolytic and genomic viruses, among others, and nanoparticles, including metallic, magnetic, polymeric, liposome, dendrimer, micelle, and others, as well as drug reuse, which is a process by which new therapeutic indications are found for existing and approved drugs. The most commonly used pharmacological categories are cardiac, antiparasitic, anthelmintic, antiviral, antibiotic, and others. For the efficient development of reused drugs, there must be a process of exchange of purposes, methods, and information already available, and for their better understanding, computational mathematical models are then used, of which the methods of blind search or screening, based on the target, knowledge, signature, pathway or network and the mechanism to which it is directed, stand out. To conclude it should be noted that these different strategies can be applied alone or in combination with each other always to improve breast cancer treatment.

PMID:34517536 | DOI:10.3934/mbe.2021316

Arch Biochem Biophys. 2021 Sep 10:109029. doi: 10.1016/j.abb.2021.109029. Online ahead of print.

ABSTRACT

Because of the critical roles of Toll-like receptors (TLRs) and receptor for advanced glycation end-products (RAGE) in the pathophysiology of various acute and chronic inflammatory diseases, continuous efforts have been made to discover novel therapeutic inhibitors of TLRs and RAGE to treat inflammatory disorders. A recent study by our group has demonstrated that trimebutine, a spasmolytic drug, suppresses the high mobility group box 1‒RAGE signaling that is associated with triggering proinflammatory signaling pathways in macrophages. Our present work showed that trimebutine suppresses interleukin-6 (IL-6) production in lipopolysaccharide (LPS, a stimulant of TLR4)-stimulated macrophages of RAGE-knockout mice. In addition, trimebutine suppresses the LPS-induced production of various proinflammatory cytokines and chemokines in mouse macrophage-like RAW264.7 cells. Importantly, trimebutine suppresses IL-6 production induced by TLR2-and TLR7/8/9 stimulants. Furthermore, trimebutine greatly reduces mortality in a mouse model of LPS-induced sepsis. Studies exploring the action mechanism of trimebutine revealed that it inhibits the LPS-induced activation of IL-1 receptor-associated kinase 1 (IRAK1), and the subsequent activations of extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and nuclear factor-κB (NF-κB). These findings suggest that trimebutine exerts anti-inflammatory effects on TLR signaling by downregulating IRAK1‒ERK1/2‒JNK pathway and NF-κB activity, thereby indicating the therapeutic potential of trimebutine in inflammatory diseases. Therefore, trimebutine can be a novel anti-inflammatory drug-repositioning candidate and may provide an important scaffold for designing more effective dual anti-inflammatory drugs that target TLR/RAGE signaling.

PMID:34517011 | DOI:10.1016/j.abb.2021.109029

PLoS Comput Biol. 2021 Sep 13;17(9):e1009384. doi: 10.1371/journal.pcbi.1009384. Online ahead of print.

ABSTRACT

Apart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases (RdRp) from the viral order Nidovirales possess two additional domains. Of these, the function of the Nidovirus RdRp associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of RdRp from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using in silico tools, we predict that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds nucleoside triphosphates at its proposed active site. Additionally, using molecular docking we have predicted the binding of three widely used kinase inhibitors and five well characterized anti-microbial compounds at the NiRAN domain active site along with their drug-likeliness. For the first time ever, using basic biochemical tools, this study shows the presence of a kinase like activity exhibited by the SARS-CoV-2 RdRp. Interestingly, a well-known kinase inhibitor- Sorafenib showed a significant inhibition and dampened viral load in SARS-CoV-2 infected cells. In line with the current global COVID-19 pandemic urgency and the emergence of newer strains with significantly higher infectivity, this study provides a new anti-SARS-CoV-2 drug target and potential lead compounds for drug repurposing against SARS-CoV-2.

PMID:34516563 | DOI:10.1371/journal.pcbi.1009384

J Biomol Struct Dyn. 2021 Sep 13:1-18. doi: 10.1080/07391102.2021.1973909. Online ahead of print.

ABSTRACT

Congenital Zika virus syndrome has caused a public health emergency of international concern. So far, there are no drugs available to prevent or treat the infection caused by Zika virus. The Zika virus NS3 helicase is a potential protein target for drug discovery due to its vital role in viral genome replication. NS3 helicase unwinds the viral RNA to enable the reproduction of the viral genome by the NS5 protein. NS3 helicase has two crucial binding sites; the ATP binding site and the RNA binding site. We used molecular docking and molecular dynamics (MD) simulations to study the structural behavior of Zika virus NS3 helicase in its apo form and in the presence of ATP, single-stranded RNA, and both ATP-RNA to understand their potential implications in NS3 helicase activity. Further, we have carried out virtual screening of FDA approved drugs, followed by molecular docking to identify the ATP-competitive hit molecules as probable Zika virus NS3 helicase inhibitors. The MD simulations trajectories were analyzed using normal mode analysis and principal component analysis that reveals fluctuations in the R-loop. These findings aid in understanding the molecular mechanisms of the simultaneous binding of ATP and RNA, and guide the design and discovery of new inhibitors of the Zika virus NS3 helicase as a promising drug target to treat the Zika virus infection. Communicated by Ramaswamy H. Sarma.

PMID:34516356 | DOI:10.1080/07391102.2021.1973909

Bioinformatics. 2021 Sep 13:btab566. doi: 10.1093/bioinformatics/btab566. Online ahead of print.

ABSTRACT

MOTIVATION: Drug repositioning reveals novel indications for existing drugs and in particular, diseases with no available drugs. Diverse computational drug repositioning methods have been proposed by measuring either drug-treated gene expression signatures or the proximity of drug targets and disease proteins found in prior networks. However, these methods do not explain which signaling subparts allow potential drugs to be selected, and do not consider polypharmacology, i.e., multiple targets of a known drug, in specific subparts.

RESULTS: Here, to address the limitations, we developed a subpathway-based polypharmacology drug repositioning method, PATHOME-Drug, based on drug-associated transcriptomes. Specifically, this tool locates subparts of signaling cascading related to phenotype changes (e.g., disease status changes), and identifies existing approved drugs such that their multiple targets are enriched in the subparts. We show that our method demonstrated better performance for detecting signaling context and specific drugs/compounds, compared to WebGestalt and clusterProfiler, for both real biological and simulated datasets. We believe that our tool can successfully address the current shortage of targeted therapy agents.

AVAILABILITY: The web-service is available at http://statgen.snu.ac.kr/software/pathome. The source codes and data are available at https://github.com/labnams/pathome-drug.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:34515762 | DOI:10.1093/bioinformatics/btab566

Curr Rev Clin Exp Pharmacol. 2021 Sep 9. doi: 10.2174/2772432816666210910104306. Online ahead of print.

ABSTRACT

AIM: The aim of the present work was to evaluate the neuroprotective potential of berberine, levetiracetam and their combination in lead acetate induced neurotoxicity by applying a drug repositioning approach.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by impairment of memory, disturbances in reasoning, planning, language and perception. Currently, there are only four drugs approved by US-FDA for AD; therefore, there is an extensive need for new drug development. The drug repositioning approach refers to the development of new uses for existing or abandoned pharmaceuticals. Several studies support the neuroprotective abilities of anti-oxidants resulting in neuronal protection against neurotoxins, suppression of oxidative stress and promotion of memory, learning and cognitive functions. Many natural polyphenols are being investigated as a potential therapeutic option for AD. Levetiracetam (LEV), a second-generation antiepileptic drug, is a new molecule that is clearly differentiated from conventional antiepileptic drugs by its pharmacologic properties. LEV also has been previously demonstrated to protect against oxidative stress-induced neurotoxicity in several models of seizures. Berberine (BBR) is an anti-inflammatory and anti-oxidant phytoconstituent.

OBJECTIVE: To study the therapeutic effect of berberine, levetiracetam and their physical mixture in lead acetate-induced neurotoxicity in Swiss albino mice for probable application in the management of Alzheimer's disease.

METHODS: Neurotoxicity was induced in Swiss albino mice by lead acetate. Behavioural parameters, such as transfer latency time and percentage alternation, were studied using Morris water maze (MWM), Elevated plus-maze test (EPM) and Y- maze for the assessment of improvement in learning and memory. Concentrations of acetylcholinesterase, MDA and GSH in the brain were also estimated. Brain samples were subjected to histopathological studies.

RESULTS: Results revealed that the combination of BBR and LEV exhibited a significant neuroprotective effect by decreasing escape latency time and increasing time spent in the target quadrant in MWM. The combination also decreases transfer latency time in EPM and acetylcholinesterase levels in the brain as compared to standard donepezil. Reduced neuronal damage was also confirmed by the histopathological report.

CONCLUSION: Leveteracitam, berberin and their combination resulted in the significant conservation of various behavioural, biochemical, enzymatic and anti-oxidant parameters that were evaluated. The neuroprotective effect of plain leveteracitam and berberin was significantly better than their combination. However, the anticipated synergism or additive effect was not observed with a combination of leveteracitam and berberin in lead acetate-induced neurotoxicity.

PMID:34515019 | DOI:10.2174/2772432816666210910104306

Arch Virol. 2021 Sep 13. doi: 10.1007/s00705-021-05223-7. Online ahead of print.

ABSTRACT

Evidence supports a role of host genetic diversity in the clinical course of coronavirus disease 2019 (COVID-19). Variation in the cannabinoid CB2 receptor gene (CNR2) could affect the regulatory action of endocannabinoids on the immune system, resulting in an increased risk of various inflammatory diseases. The present study investigated the relationship between the CNR2-Q63R variant and COVID-19 severity. A total of 200 Iranian COVID-19 patients were enrolled in the study and genotyped using a TaqMan assay. The co-dominant, dominant, recessive, over-dominant, and additive inheritance models were analyzed using SNPStats software. In silico molecular docking was also performed to simulate the effects of the Q63R variation on CB2 binding with a ligand and with the G-protein. A significant difference in the Q63R allele and genotype distribution was found between expired and discharged COVID-19 patients in co-dominant, recessive, and additive inheritance models. The molecular docking results showed that the predicted structure of mutant CB2 (63R type) could not bind to the G-protein in the correct position. The data indicated that the Q63R variation in the CNR2 gene may affect the severity of COVID-19. Identification of genes related to susceptibility and severity of COVID-19 may lead to specific targets for drug repurposing or development.

PMID:34514519 | DOI:10.1007/s00705-021-05223-7

Inform Med Unlocked. 2021;26:100725. doi: 10.1016/j.imu.2021.100725. Epub 2021 Sep 7.

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emergence has resulted in a global health crisis. As a consequence, discovering an effective therapy that saves lives and slows the spread of the pandemic is a global concern currently. In silico drug repurposing is highly regarded as a precise computational method for obtaining fast and reliable results. Transmembrane serine-type 2 (TMPRSS2) is a SARS CoV-2 enzyme that is essential for viral fusion with the host cell. Inhibition of TMPRSS2 may block or lessen the severity of SARS-CoV-2 infection. In this study, we aimed to perform an in silico drug repurposing to identify drugs that can effectively inhibit SARS-CoV-2 TMPRSS2. As there is no 3D structure of TMPRSS2 available, homology modeling was performed to build the 3D structure of human TMPRSS2. 3848 world-approved drugs were screened against the target. Based on docking scores and visual outcomes, the best-fit drugs were chosen. Molecular dynamics (MD) and density functional theory (DFT) studies were also conducted. Five potential drugs (Amikacin, isepamicin, butikacin, lividomycin, paromomycin) exhibited promising binding affinities. In conclusion, these findings empower purposing these agents.

PMID:34514079 | PMC:PMC8421083 | DOI:10.1016/j.imu.2021.100725

J Pharm Anal. 2021 Sep 4. doi: 10.1016/j.jpha.2021.09.001. Online ahead of print.

ABSTRACT

Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been found to be the culprit in the coronavirus disease (COVID-19), causing a global pandemic. Despite the existence of many vaccine programs, the number of confirmed cases and fatalities due to COVID-19 is still increasing. Furthermore, a number of variants have been reported. Because of the absence of approved anti-coronavirus drugs, the treatment and management of COVID-19 has become a global challenge. Under these circumstances, drug repurposing is an effective method to identify candidate drugs with a shorter cycle of clinical trials. Here, we summarize the current status of the application of drug repurposing in COVID-19, including drug repurposing based on virtual computer screening, network pharmacology, and bioactivity, which may be beneficial COVID-19 treatment.

PMID:34513115 | PMC:PMC8416689 | DOI:10.1016/j.jpha.2021.09.001

Front Psychiatry. 2021 Aug 26;12:681418. doi: 10.3389/fpsyt.2021.681418. eCollection 2021.

ABSTRACT

This study aimed to investigate the safety and efficacy of high-dose vitamin B6 (vB6) as an adjunct treatment for antipsychotic-induced hyperprolactinemia (AIHP) in male patients with treatment-resistant schizophrenia (TRS). In this randomized double-blinded controlled study, patients were randomized (1:1) into a control group given aripiprazole (ARI; 10 mg/day; n = 100) or an intervention group given vB6 (300 mg/12 h for 16 weeks; n = 100). Prolactin levels, psychotic symptoms [Positive and Negative Syndrome Scale (PANSS)], cognitive function [MATRICS Consensus Cognitive Battery (MCCB)], liver function, kidney function, growth hormone level, micronutrient levels, blood lipids, and adverse secondary effects (ASEs)[Treatment Emergent Symptom Scale (TESS) and Barnes-Akathisia scale] were monitored. After a 16-week treatment period, the vB6 group showed a 68.1% reduction in serum prolactin levels (from 95.52 ± 6.30 μg/L to 30.43 ± 18.65 μg/L) while the ARI group showed only a 37.4% reduction (from 89.07 ± 3.59 μg/L to 55.78 ± 7.39 μg/L). During weeks 1-4, both treatments reduced prolactin similarly. Subsequently, the ARI effect plateaued, while the vB6 effect remained robust. The vB6 group showed better alleviation of psychotic symptoms and cognitive impairment. No serious ASEs were observed; ASEs were more frequent in the ARI group. AIHP reduction efficacy of vB6 was associated with baseline prolactin and triglyceride levels, total vB6 dosage, and education level. In conclusion, compared with the ARI group, TRS patients given vB6 showed better attenuation of AIHP, lower ASE scores, and greater improvements in clinical symptoms and cognitive impairments. These results support further consideration of vB6 as a putative treatment for AIHP. Trial Registration: ChiCTR1800014755.

PMID:34512411 | PMC:PMC8426548 | DOI:10.3389/fpsyt.2021.681418

Hepatology. 2021 Sep 12. doi: 10.1002/hep.32148. Online ahead of print.

ABSTRACT

Globally, NAFLD is one of the most common liver disorders, with an estimated prevalence rate of more than 30% in men and 15% in women, and an even higher prevalence in people with type 2 diabetes mellitus. Optimal pharmacologic therapeutic approaches for NAFLD are an urgent necessity. In this study, we showed that compared to healthy controls, hepatic ACSL4 levels in NAFLD patients were found to be elevated. Suppression of ACSL4 expression promoted mitochondrial respiration, thereby enhancing the capacity of hepatocytes to mediate β-oxidation of fatty acids and to minimize lipid accumulation by up-regulating PGC1α. Moreover, we found that abemaciclib is a potent and selective ACSL4 inhibitor, low-dose of abemaciclib significantly ameliorated most of the NAFLD symptoms in multiple NAFLD mice models. Therefore, inhibition of ACSL4 is a potential alternative therapeutic approach for NAFLD.

PMID:34510514 | DOI:10.1002/hep.32148

Environ Sci Pollut Res Int. 2021 Sep 12. doi: 10.1007/s11356-021-16096-3. Online ahead of print.

ABSTRACT

Emerging from Wuhan, China, SARS-CoV-2 is the new global threat that killed millions of people, and many are still suffering. This pandemic has not only affected people but also caused economic crisis throughout the world. Researchers have shown good progress in revealing the molecular insights of SARS-CoV-2 pathogenesis and developing vaccines, but effective treatment against SARS-CoV-2-infected patients are yet to be found. Several vaccines are available and used in many countries, while many others are still in clinical or preclinical studies. However, this involves a long-term process, considering the safety procedures and requirements and their long-term protection capacity and in different age groups are still questionable. Therefore, at present, the drug repurposing of the existing therapeutics previously designed against other viral diseases seems to be the only practical approach to mitigate the current situation. The safety of most of these therapeutic agents has already been tested. Recent clinical reports revealed promising therapeutic efficiency of several drugs such as remdesivir, tenofovir disoproxil fumarate, azithromycin, lopinavir/ritonavir, chloroquine, baricitinib, and cepharanthine. Besides, plasma therapies were used to treat patients and prevent fatal outcomes. Thus, in this article, we have summarized the epidemiological and clinical data from several clinical trials conducted since the beginning of the pandemic, emphasizing the efficiency of the known agents against SARS-CoV-2 and their harmful side effects on the human body as well as their environmental implications. This review shows a clear overview of the current pharmaceutical perspective on COVID-19 treatment.

PMID:34510341 | DOI:10.1007/s11356-021-16096-3

J Thromb Thrombolysis. 2021 Sep 12. doi: 10.1007/s11239-021-02558-5. Online ahead of print.

ABSTRACT

SARS-CoV-2 represents the causative agent of the current pandemic (COVID-19). The drug repurposing technique is used to search for possible drugs that can bind to SARS-CoV-2 proteins and inhibit viral replication. In this study, the FDA-approved antiplatelets are tested against the main protease and spike proteins of SARS-CoV-2 using in silico methods. Molecular docking and molecular dynamics simulation are used in the current study. The results suggest the effectiveness of vorapaxar, ticagrelor, cilostazol, cangrelor, and prasugrel in binding the main protease (Mpro) of SARS-CoV-2. At the same time, vorapaxar, ticagrelor, and cilostazol are the best binders of the spike protein. Therefore, these compounds could be successful candidates against COVID-19 that need to be tested experimentally.

PMID:34510337 | DOI:10.1007/s11239-021-02558-5

Cancer Lett. 2021 Sep 9:S0304-3835(21)00458-4. doi: 10.1016/j.canlet.2021.09.010. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) is one of the most common malignancies worldwide, and effective therapy remains a challenge. In this study, we take advantage of a drug repurposing strategy to screen small molecules with novel anticancer activities in a small-molecule library consisting of 1056 FDA-approved drugs. We show, for the first time, that lomitapide, a lipid-lowering agent, exhibits antitumor properties in vitro and in vivo. Activated autophagy is characterized as a key biological process in lomitapide-induced CRC repression. Mechanistically, lomitapide stimulated mitochondrial dysfunction-mediated AMPK activation, resulting in increased AMPK phosphorylation and enhanced Beclin1/Atg14/Vps34 interactions, provoking autophagy induction. Autophagy inhibition or AMPK silencing significantly abrogated lomitapide-induced cell death, indicating the significance of AMPK-regulated autophagy in the antitumor activities of lomitapide. More importantly, PP2A was identified as a direct target of lomitapide by limited proteolysis-mass spectrometry (LiP-SMap), and the bioactivity of lomitapide was attenuated in PP2A-deficient cells, suggesting that the anticancer effect of lomitapide occurs in a PP2A-dependent manner. Taken together, the results of the study reveal that lomitapide can be repositioned as a potential therapeutic drug for CRC treatment.

PMID:34509534 | DOI:10.1016/j.canlet.2021.09.010

Future Med Chem. 2021 Sep 10. doi: 10.4155/fmc-2020-0273. Online ahead of print.

ABSTRACT

Background: Although some benzimidazole-based anthelmintic drugs are found to possess anticancer activity, their modes of binding interactions have not been reported. Methodology: Therefore, in this study, we aimed to investigate the binding interactions and electronic configurations of nine benzimidazole-based anthelmintics against one of the well-known cancer targets (tubulin protein). Results: Binding affinities of docked benzimidazole drugs into colchicine-binding site were calculated where flubendazole > oxfendazole > nocodazole > mebendazole. Flubendazole was found to bind more efficiently with tubulin protein than other drugs. Quantum mechanics studies revealed that the electron density of HOMO of flubendazole and mebendazole together with their molecular electrostatic potential map are closely similar to that of nocodazole. Conclusion: Our study has ramifications for considering repurposing of flubendazole as a promising anticancer candidate.

PMID:34505541 | DOI:10.4155/fmc-2020-0273

Brief Bioinform. 2021 Sep 9:bbab373. doi: 10.1093/bib/bbab373. Online ahead of print.

ABSTRACT

After experiencing the COVID-19 pandemic, it is widely acknowledged that a rapid drug repurposing method is highly needed. A series of useful drug repurposing tools have been developed based on data-driven modeling and network pharmacology. Based on the disease module, we identified several hub proteins that play important roles in the onset and development of the COVID-19, which are potential targets for repositioning approved drugs. Moreover, different network distance metrics were applied to quantify the relationship between drug targets and COVID-19 disease targets in the protein-protein-interaction (PPI) network and predict COVID-19 therapeutic effects of bioactive herbal ingredients and chemicals. Furthermore, the tentative mechanisms of candidates were illustrated through molecular docking and gene enrichment analysis. We obtained 15 chemical and 15 herbal ingredient candidates and found that different drugs may play different roles in the process of virus invasion and the onset and development of the COVID-19 disease. Given pandemic outbreaks, our method has an undeniable immense advantage in the feasibility analysis of drug repurposing or drug screening, especially in the analysis of herbal ingredients.

PMID:34505138 | DOI:10.1093/bib/bbab373

Front Genet. 2021 Aug 24;12:702259. doi: 10.3389/fgene.2021.702259. eCollection 2021.

ABSTRACT

Drug repositioning is a method of systematically identifying potential molecular targets that known drugs may act on. Compared with traditional methods, drug repositioning has been extensively studied due to the development of multi-omics technology and system biology methods. Because of its biological network properties, it is possible to apply machine learning related algorithms for prediction. Based on various heterogeneous network model, this paper proposes a method named THNCDF for predicting drug-target interactions. Various heterogeneous networks are integrated to build a tripartite network, and similarity calculation methods are used to obtain similarity matrix. Then, the cascade deep forest method is used to make prediction. Results indicate that THNCDF outperforms the previously reported methods based on the 10-fold cross-validation on the benchmark data sets proposed by Y. Yamanishi. The area under Precision Recall curve (AUPR) value on the Enzyme, GPCR, Ion Channel, and Nuclear Receptor data sets is 0.988, 0.980, 0.938, and 0.906 separately. The experimental results well illustrate the feasibility of this method.

PMID:34504515 | PMC:PMC8421679 | DOI:10.3389/fgene.2021.702259

Front Pharmacol. 2021 Aug 24;12:748886. doi: 10.3389/fphar.2021.748886. eCollection 2021.

NO ABSTRACT

PMID:34504433 | PMC:PMC8421721 | DOI:10.3389/fphar.2021.748886