RESUMO
BACKGROUND: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is an enzyme that isomerizes phosphorylated serine or threonine motifs adjacent to proline residues. Pin1 has important roles in several cellular signaling pathways, consequently impacting the development of multiple types of cancers. METHODS: Based on the previously reported inhibitory activity of pentacyclic triterpenoids isolated from the gum resin of Boswellia genus against Pin1, we designed a computational experiment using molecular docking, pharmacophore filtering, and structural clustering allied to molecular dynamics (MD) simulations and binding free energy calculations to explore the inhibitory activity of new triterpenoids against Pin1 structure. RESULTS: Here, we report different computational evidence that triterpenoids from neem (Azadirachta indica A. Juss), such as 6-deacetylnimbinene, 6-Oacetylnimbandiol, and nimbolide, replicate the binding mode of the Pin1 substrate peptide, interacting with high affinity with the binding site and thus destabilizing the Pin1 structure. CONCLUSIONS: Our results are supported by experimental data, and provide interesting structural insights into their molecular mechanism of action, indicating that their structural scaffolds could be used as a start point to develop new inhibitors against Pin1.
Assuntos
Antineoplásicos/química , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Sítios de Ligação , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , TriterpenosRESUMO
The ephedrine-based diselenide appears as a new promiscuous catalyst, able to generate optically active alcohols by addition of organozinc to aldehydes (up to 97% ee), and shows powerful GPx like activity, reducing H(2)O(2) to water in only 16.33 min (eleven times faster than PhSeSePh).
Assuntos
Efedrina/química , Glutationa Peroxidase/química , Mimetismo Molecular , Compostos Organosselênicos/química , Catálise , Desenho de Fármacos , Glutationa Peroxidase/metabolismo , EstereoisomerismoRESUMO
Ebselen is a seleno compound whose antioxidant properties have been attributed to its thiol-peroxidase and thioredoxin-like activity. However, the excessive oxidation of thiols can be potentially toxic. Thus, this work investigated whether lactate dehydrogenase (LDH) can be a possible in vitro target to the toxicity of ebselen, in comparison with diphenyl diselenide [(PhSe)(2)] and diphenyl ditelluride [(PhTe)(2)]. Ebselen was the most potent inhibitor of LDH. A maximal inhibitory effect was obtained at 2 µM to LDH purified and at 20 µM to LDH from heart and liver homogenates. Moreover, (PhSe)(2), followed by (PhTe)(2), also presented a significant inhibitory effect on LDH activity. DL-dithiothreitol (DTT) was able to revert the inhibition of LDH induced by all compounds tested, confirming the involvement of essential thiol groups on LDH inhibition by organochalcogens. In conclusion, our results show that liver and heart LDH may be a possible target for the toxicity of organochalcogens at relative low concentrations. Our results also indicate that the use of LDH, as a marker of cell viability, may be biased by a direct inhibitory effect of ebselen or other chalcogenides on LDH, resulting in false protection in an in vitro system.
Assuntos
Antioxidantes/toxicidade , Azóis/toxicidade , Derivados de Benzeno/toxicidade , L-Lactato Desidrogenase/antagonistas & inibidores , Compostos Organometálicos/toxicidade , Compostos Organosselênicos/toxicidade , Animais , Antioxidantes/química , Azóis/química , Derivados de Benzeno/química , Biomarcadores/análise , Ditiotreitol/farmacologia , Relação Dose-Resposta a Droga , Coração/efeitos dos fármacos , Isoindóis , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Estrutura Molecular , Miocárdio/enzimologia , Compostos Organometálicos/química , Compostos Organosselênicos/química , Ratos , Compostos de Sulfidrila/metabolismoRESUMO
In an environmentally friendly protocol, InI was used as a reducing agent for the Se-Se bond to prepare unsymmetrical diorganyl selenides with very short reaction times, mild conditions and excellent yields using (bmim)BF(4) as a recyclable solvent.