Dasatinib for COVID-19
Dasatinib has been reported as potentially beneficial for treatment of COVID-19. We have not reviewed these studies. See all other treatments.
Total network controllability analysis discovers explainable drugs for Covid-19 treatment, Biology Direct, doi:10.1186/s13062-023-00410-9 ,
Abstract Background The active pursuit of network medicine for drug repurposing, particularly for combating Covid-19, has stimulated interest in the concept of structural controllability in cellular networks. We sought to extend this theory, focusing on the defense rather than control of the cell against viral infections. Accordingly, we extended structural controllability to total structural controllability and introduced the concept of control hubs. Perturbing any control hub may render the cell uncontrollable by exogenous stimuli like viral infections, so control hubs are ideal drug targets. Results We developed an efficient algorithm to identify all control hubs, applying it to a largest homogeneous network of human protein interactions, including interactions between human and SARS-CoV-2 proteins. Our method recognized 65 druggable control hubs with enriched antiviral functions. Utilizing these hubs, we categorized potential drugs into four groups: antiviral and anti-inflammatory agents, drugs acting on the central nervous system, dietary supplements, and compounds enhancing immunity. An exemplification of our approach’s effectiveness, Fostamatinib, a drug initially developed for chronic immune thrombocytopenia, is now in clinical trials for treating Covid-19. Preclinical trial data demonstrated that Fostamatinib could reduce mortality rates, ICU stay length, and disease severity in Covid-19 patients. Conclusions Our findings confirm the efficacy of our novel strategy that leverages control hubs as drug targets. This approach provides insights into the molecular mechanisms of potential therapeutics for Covid-19, making it a valuable tool for interpretable drug discovery. Our new approach is general and applicable to repurposing drugs for other diseases.
A new integrated framework for the identification of potential virus–drug associations, Frontiers in Microbiology, doi:10.3389/fmicb.2023.1179414 ,
IntroductionWith the increasingly serious problem of antiviral drug resistance, drug repurposing offers a time-efficient and cost-effective way to find potential therapeutic agents for disease. Computational models have the ability to quickly predict potential reusable drug candidates to treat diseases.MethodsIn this study, two matrix decomposition-based methods, i.e., Matrix Decomposition with Heterogeneous Graph Inference (MDHGI) and Bounded Nuclear Norm Regularization (BNNR), were integrated to predict anti-viral drugs. Moreover, global leave-one-out cross-validation (LOOCV), local LOOCV, and 5-fold cross-validation were implemented to evaluate the performance of the proposed model based on datasets of DrugVirus that consist of 933 known associations between 175 drugs and 95 viruses.ResultsThe results showed that the area under the receiver operating characteristics curve (AUC) of global LOOCV and local LOOCV are 0.9035 and 0.8786, respectively. The average AUC and the standard deviation of the 5-fold cross-validation for DrugVirus datasets are 0.8856 ± 0.0032. We further implemented cross-validation based on MDAD and aBiofilm, respectively, to evaluate the performance of the model. In particle, MDAD (aBiofilm) dataset contains 2,470 (2,884) known associations between 1,373 (1,470) drugs and 173 (140) microbes. In addition, two types of case studies were carried out further to verify the effectiveness of the model based on the DrugVirus and MDAD datasets. The results of the case studies supported the effectiveness of MHBVDA in identifying potential virus-drug associations as well as predicting potential drugs for new microbes.
An interaction-based drug discovery screen explains known SARS-CoV-2 inhibitors and predicts new compound scaffolds, Scientific Reports, doi:10.1038/s41598-023-35671-x ,
AbstractThe recent outbreak of the COVID-19 pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has shown the necessity for fast and broad drug discovery methods to enable us to react quickly to novel and highly infectious diseases. A well-known SARS-CoV-2 target is the viral main 3-chymotrypsin-like cysteine protease (Mpro), known to control coronavirus replication, which is essential for the viral life cycle. Here, we applied an interaction-based drug repositioning algorithm on all protein-compound complexes available in the protein database (PDB) to identify Mpro inhibitors and potential novel compound scaffolds against SARS-CoV-2. The screen revealed a heterogeneous set of 692 potential Mpro inhibitors containing known ones such as Dasatinib, Amodiaquine, and Flavin mononucleotide, as well as so far untested chemical scaffolds. In a follow-up evaluation, we used publicly available data published almost two years after the screen to validate our results. In total, we are able to validate 17% of the top 100 predictions with publicly available data and can furthermore show that predicted compounds do cover scaffolds that are yet not associated with Mpro. Finally, we detected a potentially important binding pattern consisting of 3 hydrogen bonds with hydrogen donors of an oxyanion hole within the active side of Mpro. Overall, these results give hope that we will be better prepared for future pandemics and that drug development will become more efficient in the upcoming years.
Repurposing clinically available drugs and therapies for pathogenic targets to combat SARS‐CoV‐2, MedComm, doi:10.1002/mco2.254 ,
Multi-omics data integration and network-based analysis drives a multiplex drug repurposing approach to a shortlist of candidate drugs against COVID-19, Briefings in Bioinformatics, doi:10.1093/bib/bbab114 ,
Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is undeniably the most severe global health emergency since the 1918 Influenza outbreak. Depending on its evolutionary trajectory, the virus is expected to establish itself as an endemic infectious respiratory disease exhibiting seasonal flare-ups. Therefore, despite the unprecedented rally to reach a vaccine that can offer widespread immunization, it is equally important to reach effective prevention and treatment regimens for coronavirus disease 2019 (COVID-19). Contributing to this effort, we have curated and analyzed multi-source and multi-omics publicly available data from patients, cell lines and databases in order to fuel a multiplex computational drug repurposing approach. We devised a network-based integration of multi-omic data to prioritize the most important genes related to COVID-19 and subsequently re-rank the identified candidate drugs. Our approach resulted in a highly informed integrated drug shortlist by combining structural diversity filtering along with experts’ curation and drug–target mapping on the depicted molecular pathways. In addition to the recently proposed drugs that are already generating promising results such as dexamethasone and remdesivir, our list includes inhibitors of Src tyrosine kinase (bosutinib, dasatinib, cytarabine and saracatinib), which appear to be involved in multiple COVID-19 pathophysiological mechanisms. In addition, we highlight specific immunomodulators and anti-inflammatory drugs like dactolisib and methotrexate and inhibitors of histone deacetylase like hydroquinone and vorinostat with potential beneficial effects in their mechanisms of action. Overall, this multiplex drug repurposing approach, developed and utilized herein specifically for SARS-CoV-2, can offer a rapid mapping and drug prioritization against any pathogen-related disease.
Virtual Screening and Quantum Chemistry Analysis for SARS-CoV-2 RNA-Dependent RNA Polymerase Using the ChEMBL Database: Reproduction of the Remdesivir-RTP and Favipiravir-RTP Binding Modes Obtained from Cryo-EM Experiments with High Binding Affinity, International Journal of Molecular Sciences, doi:10.3390/ijms231911009 ,
The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the pathogenic cause of coronavirus disease 2019 (COVID-19). The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is a potential target for the treatment of COVID-19. An RdRp complex:dsRNA structure suitable for docking simulations was prepared using a cryo-electron microscopy (cryo-EM) structure (PDB ID: 7AAP; resolution, 2.60 Å) that was reported recently. Structural refinement was performed using energy calculations. Structure-based virtual screening was performed using the ChEMBL database. Through 1,838,257 screenings, 249 drugs (37 approved, 93 clinical, and 119 preclinical drugs) were predicted to exhibit a high binding affinity for the RdRp complex:dsRNA. Nine nucleoside triphosphate analogs with anti-viral activity were included among these hit drugs, and among them, remdesivir-ribonucleoside triphosphate and favipiravir-ribonucleoside triphosphate adopted a similar docking mode as that observed in the cryo-EM structure. Additional docking simulations for the predicted compounds with high binding affinity for the RdRp complex:dsRNA suggested that 184 bioactive compounds could be anti-SARS-CoV-2 drug candidates. The hit bioactive compounds mainly consisted of a typical noncovalent major groove binder for dsRNA. Three-layer ONIOM (MP2/6-31G:AM1:AMBER) geometry optimization calculations and frequency analyses (MP2/6-31G:AMBER) were performed to estimate the binding free energy of a representative bioactive compound obtained from the docking simulation, and the fragment molecular orbital calculation at the MP2/6-31G level of theory was subsequently performed for analyzing the detailed interactions. The procedure used in this study represents a possible strategy for discovering anti-SARS-CoV-2 drugs from drug libraries that could significantly shorten the clinical development period for drug repositioning.
Target-agnostic drug prediction integrated with medical record analysis uncovers differential associations of statins with increased survival in COVID-19 patients, PLOS Computational Biology, doi:10.1371/journal.pcbi.1011050 (Table 2) ,
Drug repurposing requires distinguishing established drug class targets from novel molecule-specific mechanisms and rapidly derisking their therapeutic potential in a time-critical manner, particularly in a pandemic scenario. In response to the challenge to rapidly identify treatment options for COVID-19, several studies reported that statins, as a drug class, reduce mortality in these patients. However, it is unknown if different statins exhibit consistent function or may have varying therapeutic benefit. A Bayesian network tool was used to predict drugs that shift the host transcriptomic response to SARS-CoV-2 infection towards a healthy state. Drugs were predicted using 14 RNA-sequencing datasets from 72 autopsy tissues and 465 COVID-19 patient samples or from cultured human cells and organoids infected with SARS-CoV-2. Top drug predictions included statins, which were then assessed using electronic medical records containing over 4,000 COVID-19 patients on statins to determine mortality risk in patients prescribed specific statins versus untreated matched controls. The same drugs were tested in Vero E6 cells infected with SARS-CoV-2 and human endothelial cells infected with a related OC43 coronavirus. Simvastatin was among the most highly predicted compounds (14/14 datasets) and five other statins, including atorvastatin, were predicted to be active in > 50% of analyses. Analysis of the clinical database revealed that reduced mortality risk was only observed in COVID-19 patients prescribed a subset of statins, including simvastatin and atorvastatin. In vitro testing of SARS-CoV-2 infected cells revealed simvastatin to be a potent direct inhibitor whereas most other statins were less effective. Simvastatin also inhibited OC43 infection and reduced cytokine production in endothelial cells. Statins may differ in their ability to sustain the lives of COVID-19 patients despite having a shared drug target and lipid-modifying mechanism of action. These findings highlight the value of target-agnostic drug prediction coupled with patient databases to identify and clinically evaluate non-obvious mechanisms and derisk and accelerate drug repurposing opportunities.
An in silico approach unveils the potential of antiviral compounds in preclinical and clinical trials as SARS-CoV-2 Omicron inhibitors, Saudi Journal of Biological Sciences, doi:10.1016/j.sjbs.2022.103297 ,
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