Determination of correlation times from selective and non-selective spin-lattice relaxation rates and their use in drug-drug and drug-albumin interaction studies

Abstract

Os efeitos da variação da concentração da amostra nos valores de deslocamento químico e nas velocidades de relaxação spin-rede seletiva (R1 S ) e não seletiva (R1 NS ) foram medidos em solução para os três isômeros das guanil hidrazonas derivadas do nitrobenzaldeído (NBGH) puros e com a albumina do soro bovino (BSA). Os resultados foram usados para determinar o tempo de correlação (τc), mostrando que o grau de interação intermolecular droga-droga varia com a posição do grupo nitro no anel aromático e que este grau de associação interfere na interação destas drogas com a BSA. Os resultados sugerem que o grau de interação droga-droga e droga-BSA estão relacionados com a atividade in vitro destas drogas contra o Trypanosoma cruzi.The effects of the changes in sample concentration on the NMR chemical shifts and on the selective and non-selective spin-lattice relaxation rates (R1 S and R1 NS ) of the three isomers of nitrobenzaldeyde guanyl hydrazone (NBGH) pure and with bovine serum albumin (BSA) were measured in solution. The results were used to determine the correlation times (τc), showing that the degree of intermolecular drug-drug association varies with the nitro group position on the ring and that this degree of association interferes with the interaction of these drugs with BSA. The results suggest that the degree of drug-drug and drug-BSA association are related to the in vitro anti-Trypanosoma cruzi activity of these compounds.

Theoretical and experimental 13C and 15N NMR investigation of guanylhydrazones in solution

“…It is well known that the correlation time is inversely proportional to molecular mobility. 8,39 As the compounds under study are isomers, the correlation time values obtained were similar. Then, based on statistical inefficiency calculation for 4-NBGH, 19 configurations were selected for all the compounds.…”

“…The guanylhydrazone of 4-nitrobenzaldehyde (4-NBGH) has a 50% inhibitory dose (ID 50 of 55.9 µM, whereas the ortho isomer (2-NBGH) and the meta isomer (3-NBGH) have ID 50 values of 87.5 and 182.6 µM, respectively. 6,7,8 This variation in activity may be associated with differences in the conformational freedom of the cationic side-chain, 9 which may affect the conjugation between the aromatic system and the cationic side-chain, causing electronic and structural effects on those molecules.…”

Spin-Lattice Relaxation Time in Drug Discovery and Design

“…Additionally, the determination of T 1 S and T 1 NS can be used to check if the relaxation process is dipolar or due to chemical shift anisotropy or spin rotation [36]. This methodology has been used to shed light on the affinity differences of the anti-Trypanosoma cruzi drugs orto, meta and para-nitroguanylhydrazones towards bovine serum albumin (BSA) [39]. In this example, the determination of R 1 S and R 1 NS of different concentrations of these compounds with and without BSA indicated that the lower affinity of the meta isomer is due to its stronger tendency to self association in solution.…”

“…Once a ligand has been identified, it is possible to obtain information on the binding topology as the T 1 intensity is directly related with the individual hydrogens binding effect, with the greater changes corresponding to the small molecule hydrogens localized at the molecular regions that are most involved in the interaction process [39].…”

“…The use of T 1 -related studies includes the determination of the affinity and topology of interaction of small molecules with proteins (mainly HSA and BSA) [39,50,51] and drug-micelle interaction [52][53][54][55][56].…”