Banca de DEFESA: NATALIA VITORIA PEGADO DE MEDEIROS

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : NATALIA VITORIA PEGADO DE MEDEIROS
DATE: 11/01/2022
TIME: 14:00
LOCAL: Plataforma Google Meet: meet.google.com/gei-vgvv-nsx
TITLE:

Computer-aided design of new GluN2B-Selective NMDA receptor antagonists

KEY WORDS:

NMDA antagonists: GluN2B; SNC; molecular dynamics, 3D-QSAR.

PAGES: 128
BIG AREA: Ciências da Saúde
AREA: Farmácia
SUMMARY:

The NMDA receptor is an ionotropic glutamate receptor, this Ca2+ ion channel has 4 structurally similar subunits. It is usually composed of two GluN1 (glycine binding subunit) and two GluN2 (glutamate binding subunit) subunits. 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, in order to carry out in silico studies. 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 Gefhi 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.

BANKING MEMBERS:
Externo à Instituição - EDILSON BESERRA DE ALENCAR FILHO - UNIVASF
Externa ao Programa - 1645202 - ELAINE CRISTINA GAVIOLI
Presidente - 1893445 - EUZEBIO GUIMARAES BARBOSA