Protonation, Tautomerism, and Base Pairing of the Antiviral Favipiravir (T-705)

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>

Protonation, Tautomerism, and Base Pairing of the Antiviral Favipiravir (T-705)

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>

Protonation, Tautomerism, and Base Pairing of the Antiviral Favipiravir (T-705)

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 will preferentially protonate the ring nitrogen ortho to the alcohol functional group (pKa ~ 7.4), along with protonation of the oxygen on the amide side-chain at more acidic conditions (pKa ~ 9.8). No other protomers are expected to be important. Significantly, protonation of the ring nitrogen produces an acid that can deprotonate to the enol form (pKa ~ 5.1), providing a pathway for their facile 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 7 – 8 kcal/mol, supporting previous findings that T-705 can bind with both nucleobases, leading to mis-incorporation of these pairs into viral RNA.<br>

An Assessment of Computational Methods for Calculating Accurate Structures and Energies of Bio-Relevant Polysulfur/Selenium-Containing Compounds

The heavier chalcogens sulfur and selenium are important in organic and inorganic chemistry, and the role of such chalcogens in biological systems has recently gained more attention. Sulfur and, to a lesser extent selenium, are involved in diverse reactions from redox signaling to antioxidant activity and are considered essential nutrients. We investigated the ability of the DFT functionals (B3LYP, B3PW91, ωB97XD, M06-2X, and M08-HX) relative to electron correlation methods MP2 and QCISD to produce reliable and accurate structures as well as thermochemical data for sulfur/selenium-containing systems. Bond lengths, proton affinities (PA), gas phase basicities (GPB), chalcogen–chalcogen bond dissociation enthalpies (BDE), and the hydrogen affinities (HA) of thiyl/selenyl radicals were evaluated for a range of small polysulfur/selenium compounds and cysteine per/polysulfide. The S–S bond length was found to be the most sensitive to basis set choice, while the geometry of selenium-containing compounds was less sensitive to basis set. In mixed chalcogens species of sulfur and selenium, the location of the sulfur atom affects the S–Se bond length as it can hold more negative charge. PA, GPB, BDE, and HA of selenium systems were all lower, indicating more acidity and more stability of radicals. Extending the sulfur chain in cysteine results in a decrease of BDE and HA, but these plateau at a certain point (199 kJ mol−1 and 295 kJ mol−1), and PA and GPB are also decreased relative to the thiol, indicating that the polysulfur species exist as thiolates in a biological system. In general, it was found that ωB97XD/6-311G(2d,p) gave the most reasonable structures and thermochemistry relative to benchmark calculations. However, nuances in performance are observed and discussed.

Protonated heterocyclic derivatives of cyclopropane and cyclopropanone: classical species, alternate sites, and ring fragmentation

A computational study has been performed for protonated oxygen- or nitrogen-containing heterocyclic derivatives of cyclopropane and cyclopropanone. We have searched for the most stable conformations of the protonated species using density functional theory with the B3LYP functional and the 6-31G(2df,p) basis set. More accurate enthalpy values were obtained from G4 calculations. Proton affinities and gas-phase basicities were accordingly derived.