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- W4237355590 abstract "Favipiravir (T-705) is an antiviral medication used to treat influenza. T-705 is also currently being trialled as a repurposed COVID-19 treatment. To help accelerate these efforts, this study provides important solution-phase properties of T-705 determined via computational chemistry. Density functional theory (DFT) calculations combined with the SMD continuum solvation model demonstrate that T-705 prefers the aromatic enol form in solution over the ketone tautomer. Deprotonation constants for the conjugate acids of T-705 (pKas) are then evaluated, by combining the DFT/SMD calculations with accurate G4 gas-phase basicities. These calculations indicate that T-705 is a weak base that should not significantly protonate at physiological pH. The preferential site for protonation is at the ring nitrogen ortho to the alcohol functional group (pKa ~ 7.4), followed by protonation of the oxygen on the amide side-chain at more acidic conditions (pKa ~ -9.8). Significantly, protonation of the ring nitrogen produces an acid that can deprotonate to the enol form (pKa ~ -5.1), providing a pathway for their interconversion. Finally, base-pairing of the active ribose-bound form of T-705 to cytidine and uridine is also examined. These calculations indicate that both base pairs have large binding free energies of around 4 – 5 kcal/mol, supporting previous findings that T-705 can bind with both nucleobases, leading to mis-incorporation of these pairs into viral RNA.<br>" @default.
- W4237355590 created "2022-05-12" @default.
- W4237355590 creator A5004403965 @default.
- W4237355590 date "2020-05-07" @default.
- W4237355590 modified "2023-09-28" @default.
- W4237355590 title "Protonation, Tautomerism, and Base Pairing of the Antiviral Favipiravir (T-705)" @default.
- W4237355590 doi "https://doi.org/10.26434/chemrxiv.12229122" @default.
- W4237355590 hasPublicationYear "2020" @default.
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