Entrectinib for COVID-19

COVID-19 caused by SARS-CoV-2 is a global health issue. It is yet a severe risk factor to the patients, who are also suffering from one or more chronic diseases including different lung diseases. In this study, we explored common molecular signatures for which SARS-CoV-2 infections and different lung diseases stimulate each other, and associated candidate drug molecules. We identified both SARS-CoV-2 infections and different lung diseases (Asthma, Tuberculosis, Cystic Fibrosis, Pneumonia, Emphysema, Bronchitis, IPF, ILD, and COPD) causing top-ranked 11 shared genes (STAT1, TLR4, CXCL10, CCL2, JUN, DDX58, IRF7, ICAM1, MX2, IRF9 and ISG15) as the hub of the shared differentially expressed genes (hub-sDEGs). The gene ontology (GO) and pathway enrichment analyses of hub-sDEGs revealed some crucial common pathogenetic processes of SARS-CoV-2 infections and different lung diseases. The regulatory network analysis of hub-sDEGs detected top-ranked 6 TFs proteins and 6 micro RNAs as the key transcriptional and post-transcriptional regulatory factors of hub-sDEGs, respectively. Then we proposed hub-sDEGs guided top-ranked three repurposable drug molecules (Entrectinib, Imatinib, and Nilotinib), for the treatment against COVID-19 with different lung diseases. This recommendation is based on the results obtained from molecular docking analysis using the AutoDock Vina and GLIDE module of Schrödinger. The selected drug molecules were optimized through density functional theory (DFT) and observing their good chemical stability. Finally, we explored the binding stability of the highest-ranked receptor protein RELA with top-ordered three drugs (Entrectinib, Imatinib, and Nilotinib) through 100 ns molecular dynamic (MD) simulations with YASARA and Desmond module of Schrödinger and observed their consistent performance. Therefore, the findings of this study might be useful resources for the diagnosis and therapies of COVID-19 patients who are also suffering from one or more lung diseases.

AbstractRepurposed drugs that block the interaction between the SARS-CoV-2 spike protein and its receptor ACE2 could offer a rapid route to novel COVID-19 treatments or prophylactics. Here, we screened 2701 compounds from a commercial library of drugs approved by international regulatory agencies for their ability to inhibit the binding of recombinant, trimeric SARS-CoV-2 spike protein to recombinant human ACE2. We identified 56 compounds that inhibited binding by <90%, measured the EC50 of binding inhibition, and computationally modeled the docking of the best inhibitors to both Spike and ACE2. These results highlight an effective screening approach to identify compounds capable of disrupting the Spike-ACE2 interaction as well as identifying several potential inhibitors that could serve as templates for future drug discovery efforts.

The present coronavirus disease 2019 (COVID-19) pandemic scenario has posed a difficulty for cancer treatment. Even under ideal conditions, malignancies like small cell lung cancer (SCLC) are challenging to treat because of their fast development and early metastases. The treatment of these patients must not be jeopardized, and they must be protected as much as possible from the continuous spread of the COVID-19 infection. Initially identified in December 2019 in Wuhan, China, the contagious coronavirus illness 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Finding inhibitors against the druggable targets of SARS-CoV-2 has been a significant focus of research efforts across the globe. The primary motivation for using molecular modeling tools against SARS-CoV-2 was to identify candidates for use as therapeutic targets from a pharmacological database. In the published study, scientists used a combination of medication repurposing and virtual drug screening methodologies to target many structures of SARS-CoV-2. This virus plays an essential part in the maturation and replication of other viruses. In addition, the total binding free energy and molecular dynamics (MD) modeling findings showed that the dynamics of various medications and substances were stable; some of them have been tested experimentally against SARS-CoV-2. Different virtual screening (VS) methods have been discussed as potential means by which the evaluated medications that show strong binding to the active site might be repurposed for use against SARS-CoV-2.

Repurposed drugs that block the interaction between the SARS-CoV-2 spike protein and its receptor ACE2 could offer a rapid route to novel COVID-19 treatments or prophylactics. Here, we screened 2,701 compounds from a commercial library of drugs approved by international regulatory agencies for their ability to inhibit the binding of recombinant, trimeric SARS-CoV-2 spike protein to recombinant human ACE2. We identified 56 compounds that inhibited binding in a concentration-dependent manner, measured the IC50of binding inhibition, and computationally modeled the docking of the best inhibitors to the Spike-ACE2 binding interface. The best candidates were Thiostrepton, Oxytocin, Nilotinib, and Hydroxycamptothecin with IC50’s in the 4–9 μM range. These results highlight an effective screening approach to identify compounds capable of disrupting the Spike-ACE2 interaction, as well as identify several potential inhibitors of the Spike-ACE2 interaction.