Rational Design of Novel Nucleoside Analogues for the Treatment of SARS-CoV-2 Infections

    Author Name(s)

    Diana Del Rio

    Additional Author(s)

    Kamryn Hansen
    Derek Flores

    Faculty Advisor(s)

    Dr. Ahmed Awad

    Abstract

    The RNA-dependent RNA-polymerase (RdRp) is a viral nonstructural protein that is tasked with viral transcription, replication, and is central to viral proliferation in its host. As the RdRp enzyme 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 the SARS-CoV-2 RdRp enzyme. Herein, the efficacy of novel sulfonamide-nucleoside derivatives as RdRp inhibitors is reported and compared to other reportedly effective analogues, such as remdesivir and favipiravir. Several modifications to the novel compounds, namely the addition of a triphosphate group, swapping an element with an alcohol group, and switching nitrogenous bases, were assessed. 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 the novel sulfonamide-nucleoside modifications, in particular those that possessed the triphosphate modifications, exhibited stronger binding affinity to the RdRp target compared to the known antivirals. 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. 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.

    Presentation

    Additional Materials

    Leave a Reply

    Your email address will not be published. Required fields are marked *