Estudos in silico de inibidores alostéricos do domínio amino terminal de receptores NMDA que contenham a subunidade GluN2B
The NMDA receptor is an ionotropic receptor whose main endogenous ligand is glutamate, the central pore being permeable to Ca2+ ions, and it is usually composed of 4 subunits structurally similar to each other, usually formed by two subunits of GluN1 (glycine binding subunit) and two of GluN2 (gluta...
Na minha lista:
| Autor principal: | |
|---|---|
| Outros Autores: | |
| Formato: | Dissertação |
| Idioma: | pt_BR |
| Publicado em: |
Universidade Federal do Rio Grande do Norte
|
| Assuntos: | |
| Endereço do item: | https://repositorio.ufrn.br/handle/123456789/46842 |
| Tags: |
Adicionar Tag
Sem tags, seja o primeiro a adicionar uma tag!
|
| Resumo: | The NMDA receptor is an ionotropic receptor whose main endogenous ligand is glutamate, the
central pore being permeable to Ca2+ ions, and it is usually composed of 4 subunits structurally
similar to each other, usually formed by two subunits of GluN1 (glycine binding subunit) and
two of GluN2 (glutamate binding subunit). The GluN2 subunits range from GluN2A to
GluN2D. NMDA-GluN2B receptor antagonists have shown promise in the treatment of several
diseases that affect the CNS, with lower incidences of adverse effects than non-competitive
antagonists such as ketamine. Thus, a vast literature search was carried out for molecules
already synthesized in the class. First, the molecules were separated into groups according to
their similarity. In this work, the similarity of tanimoto was used with the aid of the Gephi
program, to generate clusters. Two networks were built with this program: one showing the
affinity data measured in pKi and the other in pIC50. The most relevant groups were evaluated
in molecular dynamics simulations, in order to discover the best way to fit them into the active
site of allosteric inhibitors of NMDA receptors. Some residues have been observed as
primordial, the residues of Tyr109 and Phe114, due to the π-stacking interaction, were
extremely necessary for the interaction and, consequently, an aromatic ring in the distal portion
becomes mandatory for the structure-activity relationship of the molecule. In the opposite
portion, a benzene ring is also needed, residues like Pro177 and Phe176 accompany the
movement of that ring and also make π-type interactions, and the presence of a hydrogen bond
donor or acceptor group becomes importance for the stabilization of the molecule in the site,
the amino acids Glu236, Ser132, and Thr174 are the main ones involved. The QSAR-3D study
served to corroborate the proposed theories with the dynamics results. Two main results have
been obtained; the need for a benzene ring in the distal portion of the molecule, in which it
binds in a hydrophobic pocket, this very short or very long chain causes a drop-in activity. Some
descriptors show better values when carbon number 5 or 6 had, as a substituent, either hydrogen
bond donor groups or a methoxy group. These studies confirm and open the horizons for the
rational design of drugs for this active site, facilitating the discovery of future drugs to act on
this receptor and generate therapeutic effects for the most diverse disorders that affect the
central nervous system. |
|---|