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Diana Del Rio, Kamryn Hansen, Derek Flores, and Dr. Ahmed Awad, Department of Chemistry and Department of Biology, California State University, Channel Islands, 1 University Drive, Camarillo, CA, 92012.
RNA-dependent RNA-polymerase (RdRp) is a viral nonstructural protein (nsp) that is tasked with viral transcription and replication and is central to viral proliferation in its host. Recently, the RdRP enzyme became a key target in the search for therapeutic options against SARS-CoV-2 after the global pandemic was confirmed in March 2020. As it is tied to continuing viral replication various therapeutic options, particularly nucleoside analogues, have been tested and displayed inhibitory effects on the RdRp. The objective of this study was to propose and test new potential nucleoside analogues against SARS-CoV-2 RdRp. In this work, the efficacy of novel sulfonamide-nucleoside derivatives as RdRp inhibitors is reported and compared to other reportedly effective analogues, such as remdesivir and favipiravir. In silico molecular docking studies via internal coordinate mechanics algorithm (ICM) was utilized to assess the EDOC score, H-bonding formations and conformations of the sulfonamide-nucleosides within the catalytic pocket of RdRp. Results showed that sulfonamide-nucleosides in particular those possessed electron-withdrawing groups Cl and F exhibited stronger binding affinity to the RdRp target. Moreover, these derivatives showed enhanced binding to aspartate residues in the active site of RdRp resulting in a hypothesized disruption of electron flow, and thus interrupting the enzyme mechanism. In addition, these analogues were classified as non-AMES toxic and non-carcinogenic with excellent aqueous solubility scores of at least -3.0 logS. The predicted LD50 values of 2.413 mol/kg and 2.366 mol/kg in rats make them suitable for application in human models. In summary, the proposed compounds displayed positive enzyme-drug interactions with drug-likeness criteria that are worth further investigation as potential therapeutics against SARS-CoV-2.
Presenters: Diana Del Rio, Kamryn Hansen, Derek Flores
Institution: California State University - Channel Islands
Type: Poster
Subject: Chemistry
Status: Approved
