Pathways

Regorafenib is an oral kinase inhibitor with a broad spectrum of activity. It is used to treat metastatic colorectal cancer, advanced gastrointestinal stromal tumors, and hepatocellular carcinoma. Initially approved by the FDA on September 27, 2012, it was later expanded in April 2017 to include the treatment of hepatocellular carcinoma. Regorafenib is indicated for patients with metastatic colorectal cancer who have previously undergone various chemotherapy regimens, anti-VEGF therapy, and, if they have wild-type KRAS, anti-EGFR therapy. It is also used for patients with locally advanced, unresectable, or metastatic gastrointestinal stromal tumors who have been previously treated with imatinib mesylate and sunitinib malate. Additionally, it's prescribed for patients with hepatocellular carcinoma who have received prior treatment with sorafenib. Regorafenib functions as an inhibitor of multiple kinases, playing a role in normal cellular processes and pathological conditions like oncogenesis, tumor angiogenesis, and the maintenance of the tumor microenvironment.

Remdesivir is a nucleoside analog used to treat RNA virus infections, including COVID-19, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Remdesivir was granted FDA emergency use Authorization on May 1, 2020, for use in adults and children with suspected or confirmed COVID-19 infection requiring hospitalization. It was fully approved by the FDA on October 22, 2020 for the treatment of COVID-19. The mechanism of the drug were found to be identical between SARS-CoV, SARS-CoV-2, and MERS-CoV. Severe acute respiratory syndrome conronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19, and is a respiratory disease that is capable of progressing to viral pneumonia and acute respiratory distress syndrome (ARDS). COVID-19 can be fatal. Like other RNA viruses, SARS-CoV-2 depends on RNA-dependent RNA polymerase (RdRp) for genomic replication. Due to the much higher selectivity of mammalian DNA and RNA polymerases for ATP over remdesivir triphosphate, remdesivir is not a significant inhibitor of these mammalian enzymes. Remdesivir does, however, carry the risks for hypersensitivity reactions, including anaphylaxis, elevated transaminase levels and potential decreased efficacy when combined with hydroxychloroquine or chloroquine. SARS-CoV-2 lipoviroparticles enter target hepatocytes via receptor-mediated endocytosis. Viral RNA is released from the mature SARS-CoV-2 virion and translated at the endoplasmic reticulum. SARS-CoV-2 RNA is translated into Replicase polypotein 1ab by host ribosomes. Replicase Protein 1ab is cleaved by SARS-CoV-2 3C-like proteinase nsp5 and Papain-like protease nsp3 into various proteins required for RNA replication, mature virus synthesis, and the enzymes required for the cleavage of the polyprotein. These proteins include host translation inhibitor nsp1, non-structural protein 2, papain-like protease nsp3, non-structural protein 4, 3C-like proteinase nsp5, non-structural protein 6, non-structural protein 7, non-structural protein 8, RNA-capping enzyme subunit nsp9, non-structural protein 10, RNA-directed RNA polymerase nsp12, helicase nsp13, guanine-N7 methyltransferase nsp14, uridylate-specific endoribonuclease nsp15, and 2'-O-methyltransferase nsp16. SARS-CoV-2 RNA that was released from the virus is normally replicated by RNA polymerase which is comprised of nsp7, nsp8, and nsp12. Remdesivir is a phosphoramidite produg of a 1'-cyano-substituted adenosine nucleoside analogue that competes with ATP for incorporation into newly synthesized viral RNA by the RdRp complex. Remdesivir is cleaved to a monophosphate form through the actions of either carboxylesterase 1 or cathepsin A enzymes. Remdesivir nucleoside monophosphate is then phosphylated by undescribed kinases to remdesivir nucleoside triphosphate. Remdesivir Nucleoside Triphosphate inhibits RNA polymerase, by competing with ATP for incorporation into newly synthesized viral RNA. This prevents RNA replication from occurring. Because RNA replication does not occur, mature, infective viruses are unable to be assembled and released.

Metabolites of Remdesivir are predicted with biotransformer.

Remifentanil is a pharmacologically-active, synthetic, small molecule derived from fentanyl and belongs to a class of drugs called opioids. Opioids are therapeutically employed to achieve analgesia. Remifentanial’s rapid mechanism of action primarily involves its agonistic effects on mu-type opioid receptors which are inhibitory G-coupled protein receptors and lead to the inhibition of adenylate cyclase and decrease in cAMP production. Analgesia, anesthesia, and respiratory depression are a function of remifentanial’s action on these mu-type opioid receptors.