Estudos in silico de inibidores alostéricos do domínio amino terminal de receptores NMDA que contenham a subunidade GluN2B

• Main Author: Medeiros, Natalia Vitória Pegado de
• Publication Date: 2022
• Format: Master thesis
• Language: por
• Source: Repositório Institucional da UFRN
• dARK ID: ark:/41046/001300000d2m3
• Download full: https://repositorio.ufrn.br/handle/123456789/46842
• topic: N-Metilaspartato (NMDA); GluN2B; Docking; Dinâmica molecular; MM-PBSA; QSAR

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.