On the interactions of leflunomide and teriflunomide within receptor cavity — NMR studies and energy calculations

Abstract

Leflunomide is a disease-modifying antirheumatic drug with antiinflammatory and immunosuppressive activity used for the treatment of psoriatic and rheumatoid arthritis. It undergoes rapid metabolization to teriflunomide, a metabolite that is responsible for the biological activity of leflunomide. Continuing our investigations on the interactions of biologically important azahetarenes with the environment, we focused on leflunomide and its active metabolite, teriflunomide, considering the interactions teriflunomide–amino acid within the target protein (dihydroorotate dehydrogenase) using density functional theory, as well as ONIOM techniques. The results of theoretical studies have shown that the interactions of teriflunomide with tyrosine and arginine involve principally the amide fragment of teriflunomide. The presence of the internal hydrogen bond between (Z)-teriflunomide carbonyl oxygen and enolic hydroxyl decreases the interaction strength between teriflunomide and tyrosine or arginine. Even the E isomer of teriflunomide would usually provide a stronger interaction teriflunomide—amino acid than the Z isomer with the internal hydrogen bond.Graphical AbstractThe interactions of leflunomide and teriflunomide within receptor cavityᅟElectronic supplementary materialThe online version of this article (doi:10.1007/s00894-015-2643-z) contains supplementary material, which is available to authorized users.

Possible interactions between fused pyrazole derivative and magnesium ions - NMR experiments and theoretical calculations

“…It is noteworthy that the dielectric constant values of water and DMSO are on a comparable level (ε = 78.3 and 46.8, respectively). 26,27,34 Moreover, the results of the NMR calculations carried out using DMSO as a solvent in comparison with the corresponding data for water are very similar. Table 2.…”

“…The shifts of compound 7 and reference TMS were calculated using the same method whereas the reference TMS was used to obtain the chemical shifts of 1 according to the following equation: δi = σref − σi, where δi was the chemical shift of i-nuclei of 1 and σref and σi were the calculated isotropic magnetic shielding tensor for the TMS and 1, respectively. 26,27,50 The calculated chemical shifts for the homotopic protons were averaged. The Chemcraft 1.7 software was utilized for visualization of all optimized rotamers.…”

“…25 The analysis of chemical shifts before and after the complexation with Mg 2+ led to the conclusion that the most susceptible indazole region for the interaction with the metal ion is the NH functionality and position 5 of the ring. In a continuation of our attempts to clarify the anticancer mechanism of the condensed pyrazoles, 26,27 we present herein our theoretical studies concerning interactions of another fused pyrazole derivative with magnesium cations. We also focused on calculations of the proton chemical shifts of this azole by applying various basis sets and methods in gaseous phase.…”

Investigations on Synperiplanar and Antiperiplanar Isomers of Losartan: Theoretical and Experimental NMR Studies

“…Particular clusters with water molecules were constructed by adding water molecules to protons of hydroxyl and methyl groups and then optimized. In order to discriminate the protons in 1 , they were marked according to Figure 1 positions (experimental values of chemical shifts are given in ppm and are in good agreement with reference data [10]; Figures S22–S24, Supplementary Materials): 1 H-NMR (DMSO- d 6 , 400 MHz, 293 K) ppm: I 7.553 (H7; 1H; d; 3 J HH = 9.2 Hz), J 7.370 (H6, H8; 2H; m; overlapping signals), K 7.293 (H5; 1H; d; 3 J HH = 9.2 Hz), H 7.108 (H2, H4; 2H; d; 3 J HH = 8.0 Hz), G 6.917 (H1, H3; 2H; d; 3 J HH = 8.0 Hz), F 5.228 (H9, H10; 2H; s), OH 5.304 (H13, 1H, t, 3 J HH = 5.2 Hz), E 4.328 (H11, H12; 2H; d; 3 J HH = 4.8 Hz), D 2.51 (H14, H15; 2H, s), C 1.497 (H16, H17; 2H; m), B 1.270 (H19, H18; 2H; m), A 0.826 (H22–H20; 3H; t; 3 J HH = 7.6 Hz). The 1 H-NMR spectra were recorded in DMSO- d 6 .…”

“…The authors described the discrepancies between the calculated and experimental results; however, calculations were carried out for an isolated losartan molecule in the gaseous phase. Continuing our computational chemistry investigations on biologically-active azoles [9,10,11], we focused our attention on calculation of the chemical shifts of losartan ( 1 H-NMR spectrum) applying different basis sets and methods in the gaseous phase and using the conductor-like polarizable continuum model (CPCM) solvation model, so that the influence of the solvent environment is also accounted for. Apart from the DFT formalism, losartan was also investigated using molecular dynamics (MD) techniques [5,12].…”