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

2020 ◽  
Author(s):  
Gabriel da Silva
Keyword(s):  
Density Functional ◽  
Enol Form ◽  
Free Energies ◽  
Base Pairing ◽  
Base Pairs ◽  
Functional Theory ◽  
Important Solution ◽  
Ring Nitrogen ◽  
Acidic Conditions ◽  
Gas Phase Basicities

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>

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

2020 ◽  
Author(s):  
Gabriel da Silva
Keyword(s):  
Density Functional ◽  
Enol Form ◽  
Free Energies ◽  
Base Pairing ◽  
Base Pairs ◽  
Functional Theory ◽  
Important Solution ◽  
Ring Nitrogen ◽  
Acidic Conditions ◽  
Gas Phase Basicities

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)

2020 ◽  
Author(s):  
Gabriel da Silva
Keyword(s):  
Density Functional ◽  
Enol Form ◽  
Free Energies ◽  
Base Pairing ◽  
Base Pairs ◽  
Functional Theory ◽  
Important Solution ◽  
Ring Nitrogen ◽  
Acidic Conditions ◽  
Gas Phase Basicities

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>

scholarly journals The Energetic Viability of Δ1-Piperideine Dimerization in Lysine-derived Alkaloid Biosynthesis

Metabolites ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. 48 ◽  
Author(s):  
Hajime Sato ◽  
Masanobu Uchiyama ◽  
Kazuki Saito ◽  
Mami Yamazaki
Keyword(s):  
Density Functional ◽  
Indole Alkaloid ◽  
Alkaloid Biosynthesis ◽  
Functional Theory ◽  
The Density Functional Theory ◽  
Reaction Proceeds ◽  
Acidic Conditions ◽  
Dimerization Reaction ◽  
Available Information ◽  
Skeleton Formation

Lys-derived alkaloids widely distributed in plant kingdom have received considerable attention and have been intensively studied; however, little is known about their biosynthetic mechanisms. In terms of the skeleton formation, for example, of quinolizidine alkaloid biosynthesis, only the very first two steps have been identified and the later steps remain unknown. In addition, there is no available information on the number of enzymes and reactions required for their skeletal construction. The involvement of the Δ 1 -piperideine dimerization has been proposed for some of the Lys-derived alkaloid biosyntheses, but no enzymes for this dimerization reaction have been reported to date; moreover, it is not clear whether this dimerization reaction proceeds spontaneously or enzymatically. In this study, the energetic viability of the Δ 1 -piperideine dimerizations under neutral and acidic conditions was assessed using the density functional theory computations. In addition, a similar type of reaction in the dipiperidine indole alkaloid, nitramidine, biosynthesis was also investigated. Our findings will be useful to narrow down the candidate genes involved in the Lys-derived alkaloid biosynthesis.

scholarly journals Popular Integration Grids Can Result in Large Errors in DFT-Computed Free Energies

2019 ◽  
Author(s):  
Andrea N. Bootsma ◽  
Steven Wheeler
Keyword(s):  
Transition State ◽  
Molecular Orientation ◽  
Density Functional ◽  
Basis Sets ◽  
Free Energies ◽  
Functional Theory ◽  
Metal Free ◽  
Stereoselective Reactions ◽  
Functionalization Reaction ◽  
Transition State Structures

<div>Density functional theory (DFT) has emerged as a powerful tool for analyzing organic and organometallic systems and proved remarkably accurate in computing the small free energy differences that underpin many chemical phenomena (e.g. regio- and stereoselective reactions). We show that the lack of rotational invariance of popular DFT integration grids reveals large uncertainties in computed free energies for isomerizations, torsional barriers, and regio- and stereoselective reactions. The result is that predictions based on DFT-computed free energies for many systems can change qualitatively depending on molecular orientation. For example, for a metal-free propargylation of benzaldehyde, predicted enantioselectivities based on B97-D/def2-TZVP free energies using the popular (75,302) integration grid can vary from 62:38 to 99:1 by simply rotating the transition state structures. Relative free energies for the regiocontrolling transition state structures for an Ir-catalyzed C–H functionalization reaction computed using M06/6-31G(d,p)/LANL2DZ and the same grid can vary by more than 5 kcal mol–1, resulting in predicted regioselectivities that range anywhere from 14:86 to >99:1. Errors of these magnitudes occur for different functionals and basis sets, are widespread among modern applications of DFT, and can be reduced by using much denser integration grids than commonly employed.</div>

Impact of N-(2-aminoethyl) Glycine Unit on Watson-Crick Base Pairs

2019 ◽  
Vol 233 (3) ◽  
pp. 449-469 ◽  
Author(s):  
Indumathi Karunakaran ◽  
Abiram Angamuthu ◽  
Praveena Gopalan
Keyword(s):  
Density Functional ◽  
Structural Parameters ◽  
Base Pairs ◽  
Functional Theory ◽  
Amide Bonds ◽  
Highest Occupied Molecular Orbital ◽  
Minimal Distortion ◽  
Stabilization Energies ◽  
The Stability ◽  
Lowest Unoccupied Molecular Orbitals

Abstract We aim to understand the structure and stability of the backbone tailored Watson-Crick base pairs, Guanine-Cytosine (GC), Adenine-Thymine (AT) and Adenine-Uracil (AU) by incorporating N-(2-aminoethyl) glycine units (linked by amide bonds) at the purine and pyrimidine sites of the nucleobases. Density functional theory (DFT) is employed in which B3LYP/6-311++G∗∗ level of theory has been used to optimize all the structures. The peptide attached base pairs are compared with the natural deoxyribose nucleic acid (DNA)/ribonucleic acid (RNA) base pairs and the calculations are carried out in both the gas and solution phases. The structural propensities of the optimized base pairs are analyzed using base pair geometries, hydrogen bond distances and stabilization energies and, compared with the standard reference data. The structural parameters were found to correlate well with the available data. The addition of peptide chain at the back bone of the DNA/RNA base pairs results only with a minimal distortion and hence does not alter the structural configuration of the base pairs. Also enhanced stability of the base pairs is spotted while adding peptidic chain at the purine site rather than the pyrimidine site of the nucleobases. The stability of the complexes is further interpreted by considering the hydrogen bonded N–H stretching frequencies of the respective base pairs. The discrimination in the interaction energies observed in both gas and solution phases are resulted due to the existence of distinct lowest unoccupied molecular orbitals (LUMO) in the solution phase. The reactivity of the base pairs is also analyzed through the in-depth examinations on the highest occupied molecular orbital (HOMO)-LUMO orbitals.

scholarly journals Computational Study of Methane C–H Activation by Main Group and Mixed Main Group–Transition Metal Complexes

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2794
Author(s):  
Carly C. Carter ◽  
Thomas R. Cundari
Keyword(s):  
Transition Metal Complexes ◽  
Active Site ◽  
Density Functional ◽  
Computational Study ◽  
Divalent Metal ◽  
Main Group ◽  
Free Energies ◽  
Functional Theory ◽  
Activation Barriers ◽  
Experimental Values

In the present density functional theory (DFT) research, nine different molecules, each with different combinations of A (triel) and E (divalent metal) elements, were reacted to effect methane C–H activation. The compounds modeled herein incorporated the triels A = B, Al, or Ga and the divalent metals E = Be, Mg, or Zn. The results show that changes in the divalent metal have a much bigger impact on the thermodynamics and methane activation barriers than changes in the triels. The activating molecules that contained beryllium were most likely to have the potential for activating methane, as their free energies of reaction and free energy barriers were close to reasonable experimental values (i.e., ΔG close to thermoneutral, ΔG‡ ~30 kcal/mol). In contrast, the molecules that contained larger elements such as Zn and Ga had much higher ΔG‡. The addition of various substituents to the A–E complexes did not seem to affect thermodynamics but had some effect on the kinetics when substituted closer to the active site.

pH-related fluorescence quenching mechanism of pterin derivatives and the effects of 6-site substituents

2018 ◽  
Vol 96 (4) ◽  
pp. 404-410
Author(s):  
Lei Liu ◽  
Bingqing Sun
Keyword(s):  
Density Functional Theory ◽  
Hydrogen Bonding ◽  
Fluorescence Quenching ◽  
Density Functional ◽  
Relaxation Processes ◽  
Quenching Mechanism ◽  
Functional Theory ◽  
Td Dft ◽  
Fluorescence Quenching Mechanism ◽  
Acidic Conditions

2-Amino-4-hydroxypteridine (pterin) and its derivatives serve as photooxidants and exhibit strong fluorescence. When they interact with hydrogen acceptors such as acetate and phosphate, their fluorescences are significantly quenched in acidic conditions (pH 4.9–5.5) but are retained in basic conditions (pH 10.0–10.5). This pH-related fluorescence quenching mechanism of pterin and its derivatives are fully investigated by using density functional theory (DFT) and time-dependent density functional theory (TD-DFT). Pterin and its derivatives are demonstrated to show favorable excited-state proton transfer (ESPT) abilities in acidic conditions that induce the experimentally observed fluorescence quenching. In contrast, the ESPT processes are found to be retarded due to the lack of strong hydrogen-bonding interactions in basic environments, which sustain their fluorescence. Interestingly, these ESPT processes are found to show different site specificities depending on the 6-site substituents. The introduction of electron-donating substituent activates the N1 site, making it the preferred ESPT site. By contrast, the introduction of an electron-withdrawing substituent activates the N5 site, making it the favorable ESPT site. The substitutions of different functional groups are found to affect the locations of acidic centers during the excitation and relaxation processes. This further affects the hydrogen-bonding patterns and ultimately brings site specificity to the ESPT process.

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