Theoretical Insights into the Effect of Halogenated Substituent on the Electronic Structure and Spectroscopic Properties of the Favipiravir Tautomeric Forms and Its Implications on the Treatment of COVID-19

Abstract

<p>In this study, we systematically investigated the electronic structure, spectroscopic (nuclear magnetic resonance, infrared, Raman, electron ionization mass spectrometry, UV-Vis, circular dichroism, and emission) properties, and tautomerism of halogenated favipiravir compounds (fluorine, chlorine, and bromine) from a computational perspective. Additionally, the effects of hydration on the proton transfer mechanism of the tautomeric forms of the halogenated favipiravir compounds are discussed. Our results suggest that spectroscopic properties allow for the elucidation of such tautomeric forms. As is well-known, the favipiravir compound has excellent antiviral properties and hence was recently tested for the treatment of new coronavirus (SARS-CoV-2). Through in silico modeling, in the current study, we evaluate the role of such tautomeric forms in order to consider the effect of drug-metabolism into the inhibition process of the main protease (M<sup>pro</sup>) and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 virus. These findings clearly indicated that all title compounds are better as RNA-inhibiting.</p>

Effect of drug metabolism in the treatment of SARS-CoV-2 from an entirely computational perspective

“…In our previous work, we estimated the EI-MS spectra and identi ed the possible trajectories for the Favipiravir molecule and its tautomers. 12 In the current work, we expanded our analysis to evaluate each intermediary species' biochemical activity. The computed EI-MS spectrum of Favipiravir has two main trajectories that yield similar species (Figure 1 (a)).…”

“…37 As a result, it is important to note that the values extracted from RMSD (5R82 = 0.94 Ǻ / 3H5Y = 1.55 Ǻ) showed that the program used in this study is adequate for predicting the conformation that the co-crystallized ligands adopted experimentally within the viral M pro and RdRp of SARS-CoV-2. 12,13,38 The re-docking con gurations were maintained to perform the docking calculations of the drugs investigated as well as their metabolism fragments. All computed interaction energy results are exhibited in Table 1.…”

“…36 The crystallographic M pro and RdRp structures used in this simulations were prepared according to our previous studies. 12,13,39 Based on this strategy, we also investigate the absorption, distribution, mechanism, excretion, and toxicity (ADMET) properties for antiviral target drugs and their by-products metabolic. Thereby, the acute toxicity and other relevant pharmacokinetics parameters can easily be obtained from a rat model-based admetSAR predictor (http://biosig.unimelb.edu.au/pkcsm/prediction).…”

“…This ADMET procedure has been used previously in similar systems with large success. 12,13,38 Declarations Figures…”

“…Possible candidates for the treatment of COVID-19 include the antiviral drugs Favipiravir, Galidesivir, Nitazoxanide, Remdesivir, Ribavirin, Chloroquine, and Hydroxychloroquine due to their ability for the enzymatic inhibition of SARS-CoV-2. [7][8][9][10][11][12][13] In addition to the effectiveness of a particular drug in the treatment of a disease, drug design must also consider xenobiotics, or the mechanism via which the by-products of a medicine interact with and exit the human body. [14][15][16][17] As is well known, the general mechanism of xenobiotics involves three main phases: Phase I, drug activation through oxidation, reduction, and hydrolysis; Phase II, drug inactivation by means of conjugation with proteins to yield water-soluble metabolites that can be eliminated from the body; and Phase III, biotransformation by enzymes before the waste leaves the body.…”