Banca de QUALIFICAÇÃO: JOSE XAVIER DE LIMA NETO

Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.
DISCENTE : JOSE XAVIER DE LIMA NETO
DATA : 21/05/2018
HORA: 09:00
LOCAL: Sala Catolé
TÍTULO:

Mapping key interactions in G protein-coupled receptors: a study at receptors A class and C class

PALAVRAS-CHAVES:

GPCR, serotonin, GABA, binding energy, MFCC

PÁGINAS: 126
GRANDE ÁREA: Ciências Biológicas
ÁREA: Bioquímica
RESUMO:

G protein-coupled receptors (GPCRs) constitute the major protein superfamily of the human genome, with its presence shown in a large taxonomic distribution. Due their wide distribution, it is easy to realize the engagement of these proteins in many metabolic pathways and, consequently, a large amount of cell disturbs are directly connected to GPCR dysfunctions. In this sense, pharmaceutical industry has GPCRs as its main target, accounting with 30%-50% of all drugs marketed worldwide. Serotonin receptors (5-HTR), a class A GPCR, are one of the major therapeutic targets. 5-HT 1B receptors have been aiming to the treatment of migraine, since them act in the vasoconstriction of brain vessels. However, due to the structural similarity with other monoaminergic receptors, severe side-effects have been reported, reinforcing the need for methods to distinguish these receptors at a molecular level. On the other hand, the class C receptors are potent neuromodulators, but little attention was dedicated to them. These receptors show the same structural feature depicted by other GPCRs at the transmembrane domain, thought the binding site to agonists and antagonists is in the extracellular N-terminal, named Venus fly trap, which is closed after agonist binds. Among class C receptors, GABAB acts as potent neuronal signal inhibitors, leading the impairment of neurotransmitters release and closing the ionic gates. Despite its importance, only baclofen was approved by FDA to be sold as a GABAB modulator, acting to treat neuropatic pain. Thus, this work propose an evaluation of interactions made by compound that bind 5-HT1B and GABAB at a quantum level, aiming attain a deeper knowledge and describe the key point to recognition and docking of these molecules at the binding site. Therefore, we take full advantage of the crystallographic structure of both receptors, applying the electrostatic embedding molecular fractionation with conjugate caps method (EE-MFCC) to cut the proteins into small amino-acids to posterior quantum calculations. Our results presented a way to predict the relevance of amino-acids that compose the binding site for 5-HT1B and GABAB, among them we can mention the residues: ASP129, ASP352, ASP123, GLU198, ASP204, PHE330, LEU126, PHE351, ILE130, VAL201, VAL200, THR355 e ARG114, making part of the serotonin receptor binding site for dihydroergotamine, and ER130, GLY151, SER153, HIS170, TYR250, TRP278, GLU349, VAL201, SER152, SER154, GLN348, ARG168 e TRP65, the residues with the highest importance to baclofen and 2-hydroxysaclofen docking on GABAB. Through these data, it was possible identify and describe the most important ligand and protein regions, besides permit a differentiation in a molecular and energetic level of the affinity obtained experimentally to the ligands here studied.

MEMBROS DA BANCA:
Presidente - 1513597 - JOAO PAULO MATOS SANTOS LIMA
Interno - 1507794 - RODRIGO JULIANI SIQUEIRA DALMOLIN
Externo à Instituição - YWLLIANE DA SILVA RODRIGUES MEURER - UFRN