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Predicting 19 F?NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase-Inhibitor Complex.

ABSTRACT: The absence of fluorine from most biomolecules renders it an excellent probe for NMR spectroscopy to monitor inhibitor-protein interactions. However, predicting the binding mode of a fluorinated ligand from a chemical shift (or vice versa) has been challenging due to the high electron density of the fluorine atom. Nonetheless, reliable 19 F chemical-shift predictions to deduce ligand-binding modes hold great potential for in?silico drug design. Herein, we present a systematic QM/MM study to predict the 19 F?NMR chemical shifts of a covalently bound fluorinated inhibitor to the essential oxidoreductase tryparedoxin (Tpx) from African trypanosomes, the causative agent of African sleeping sickness. We include many protein-inhibitor conformations as well as monomeric and dimeric inhibitor-protein complexes, thus rendering it the largest computational study on chemical shifts of 19 F nuclei in a biological context to date. Our predicted shifts agree well with those obtained experimentally and pave the way for future work in this area.

SUBMITTER: Dietschreit JCB

PROVIDER: S-EPMC7496126 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Predicting <sup>19</sup> F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase-Inhibitor Complex.

Dietschreit Johannes C B JCB Wagner Annika A Le T Anh TA Klein Philipp P Schindelin Hermann H Opatz Till T Engels Bernd B Hellmich Ute A UA Ochsenfeld Christian C

Angewandte Chemie (International ed. in English) 20200525 31

The absence of fluorine from most biomolecules renders it an excellent probe for NMR spectroscopy to monitor inhibitor-protein interactions. However, predicting the binding mode of a fluorinated ligand from a chemical shift (or vice versa) has been challenging due to the high electron density of the fluorine atom. Nonetheless, reliable <sup>19</sup> F chemical-shift predictions to deduce ligand-binding modes hold great potential for in silico drug design. Herein, we present a systematic QM/MM st ...[more]

PMID: 32239740

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Project description:Detailed solvent and temperature effects on the experimental 1H-NMR chemical shifts of the natural products chrysophanol (1), emodin (2), and physcion (3) are reported for the investigation of hydrogen bonding, solvation and conformation effects in solution. Very small chemical shift of ???? < 0.3 ppm and temperature coefficients ???/??? ? 2.1 ppb/K were observed in DMSO-d6, acetone-d6 and CDCl3 for the C(1)-OH and C(8)-OH groups which demonstrate that they are involved in a strong intramolecular hydrogen bond. On the contrary, large chemical shift differences of 5.23 ppm at 298 K and ??/?? values in the range of -5.3 to -19.1 ppb/K between DMSO-d6 and CDCl3 were observed for the C(3)-OH group which demonstrate that the solvation state of the hydroxyl proton is a key factor in determining the value of the chemical shift. DFT calculated 1H-NMR chemical shifts, using various functionals and basis sets, the conductor-like polarizable continuum model, and discrete solute-solvent hydrogen bond interactions, were found to be in very good agreement with the experimental 1H-NMR chemical shifts even with computationally less demanding level of theory. The 1H-NMR chemical shifts of the OH groups which participate in intramolecular hydrogen bond are dependent on the conformational state of substituents and, thus, can be used as molecular sensors in conformational analysis. When the X-ray structures of chrysophanol (1), emodin (2), and physcion (3) were used as input geometries, the DFT-calculated 1H-NMR chemical shifts were shown to strongly deviate from the experimental chemical shifts and no functional dependence could be obtained. Comparison of the most important intramolecular data of the DFT calculated and the X-ray structures demonstrate significant differences for distances involving hydrogen atoms, most notably the intramolecular hydrogen bond O-H and C-H bond lengths which deviate by 0.152 t? 0.132 Å and 0.133 to 0.100 Å, respectively, in the two structural methods. Further differences were observed in the conformation of -OH, -CH3, and -OCH3 substituents.

Dataset Information

Predicting 19 F?NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase-Inhibitor Complex.

Publications

Predicting <sup>19</sup> F NMR Chemical Shifts: A Combined Computational and Experimental Study of a Trypanosomal Oxidoreductase-Inhibitor Complex.

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