Repurposing of gastric cancer drugs against COVID-19

Abstract

Corona Virus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has become a global pandemic. Additionally, the SARS-CoV-2 infection in the patients of Gastric Cancer (GC; the third leading cause of death in the world) pose a great challenge for the health management of the patients. Since there have been uncertainties to develop a new drug against COVID-19, there is an urgent need for repurposing drugs that can target key proteins of both SARS-CoV-2 and GC. The SARS-CoV-2-RdRp protein contains the NiRAN domain, which is known to have kinase-like folds. A docking study of the FDA approved drugs against GC was performed using AutoDock 4.2 and Glide Schrodinger suite 2019 against SARS-CoV-2-RdRp protein. MMGBSA and MD simulation studies were performed to investigate the binding and stability of the inhibitors with the target protein. In this study, we have found 12 kinase inhibitors with high binding energies namely Baricitinib, Brepocitinib, Decernotinib, Fasudil, Filgotinib, GSK2606414, Peficitinib, Ruxolitinib, Tofacitinib, Upadacitinib, Pamapimod and Ibrutinib. These FDA approved drugs against GC can play a key role in the treatment of COVID-19 patients along with GC as comorbidity. We also hypothesize that JAK, ITK, Rho-associated kinases, FGFR2, FYN, PERK, TYK2, p38-MAPK and SYK kinases can be considered as key therapeutic targets in COVID-19 treatment. Taken altogether, we have proposed the SARS-CoV-2-RdRp as a potential therapeutic target through in-silico studies. However, further in-vitro and in-vivo studies are required for the validation of the proposed targets and drugs for the treatment of COVID-19 patients already suffering from GC.

JAK inhibitors and COVID-19

“…Of interest an in-silico docking study found significant binding of kinase inhibitors like upadacitinib to the RNA dependent RNA polymerase kinase-like folded NiRAN domain. 135 …”

Systems biology models to identify the influence of SARS-CoV-2 infections to the progression of human autoimmune diseases

“… Hub Gene Degree Closeness Centrality Betweenness Centrality Remarks Ref FYN 25 0.52406417 0.29810382 Considered as key kinase inhabitor and medicinal targets for COVID-19 remedy; engaged in the release of the proinflammatory cytokines, therefore leads to the initiation of COVID-19; found highly occupied in CD 4 + T cells from SLE patients and connectivity with COVID-19 theraputics. [ [47] , [48] , [49] , [50] ] VEGFA 22 0.46666667 0.11766869 Stayed upregulated in lung infected paitents who have died from COVID-19 and recognized as conceivable theraputic target for COVID-19 treatment; acquired highly enriched in AD activities and severity. [ 51 , 52 ] CTNNB1 22 0.44545455 0.13809635 Identified as gene control target of miRNAs encoded from SARS-CoV-2; Identified as a diagnostic biomarker for RA.…”

“…Kinase inhibitors are the major substance of human body that control funcitoning, cell signaling and many other processes. Recent studies have discovered FYN to be a prominent kinase inhibitor and a therapeutic target for COVID-19 in order to manage the infectious life cycle and mitigate lung-damaging signs of illness [ 47 , 48 ]. Clinically pro-inflammatory cytokine IL-6 was shown functioning at an elevated concentration in the pathophysiology of COVID-19 [ 47 , 51 ].…”

“…Recent studies have discovered FYN to be a prominent kinase inhibitor and a therapeutic target for COVID-19 in order to manage the infectious life cycle and mitigate lung-damaging signs of illness [ 47 , 48 ]. Clinically pro-inflammatory cytokine IL-6 was shown functioning at an elevated concentration in the pathophysiology of COVID-19 [ 47 , 51 ]. FYN, one of the hub proteins, initiates a phosphorylation immunorceptive motive of tyrosine-based motivation, eventually leading to the release of IL-6 proinflammatory cytokines.…”

The Role of Unfolded Protein Response in Coronavirus Infection and Its Implications for Drug Design

“…Small molecules targeting the PERK branch include GSK2606414, Salubrinal, GSK2656157, ISRIB, Guanabenz, Sepin1, Trazodone Hydrochloride, and Dibenzoylmethane, with SARS-CoV-2, but it was excluded from the study since its ability to be carcinogenic (Sonkar et al, 2021). GSK2606414 treatment of MHV-infected cells revealed a relief of translation inhibition (Echavarria-Consuegra et al, 2021).…”