Banca de DEFESA: JOSE XAVIER DE LIMA NETO

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
DISCENTE : JOSE XAVIER DE LIMA NETO
DATA : 04/01/2019
HORA: 14:00
LOCAL: Sala da Física - Departamento de Biofísica
TÍTULO:

Quantum Biochemistry of Medicinal Drugs

PALAVRAS-CHAVES:

gpcrs, mfcc, interactionenergy, serotonin, gaba, imunotherapy

PÁGINAS: 140
GRANDE ÁREA: Ciências Biológicas
ÁREA: Bioquímica
RESUMO:

The drug development process have been improved by the add of other knowledge areas in the field of pharmaceutical sciences. Among these improvements, the introduction of the computational simulation was, with no doubt, one of the greatest landmarks for the field’s development. Nowadays, there are two main targets in drug development, the G protein-coupled receptors (GPCRs) and the immunotherapeutics. 5-HT1B receptors have been targeted for the treatment of migraine, since they act in the brain arteries contraction. By the other hand, class C GPCRs are potent neuromodulators, though small attention has been dedicated to them, such as the GABAB receptors. These receptor acts as potent inhibitors of the neuronal signal, leadind to impairments in the neurotransmitters release and closure of ionic channels. Despite its pharmacological relevance, only baclofen is approved by US-FDA as a molecule targeting GABAB, being used to treat neuropathic pain. For the class of immunotherapeutics, the most remarkable are the monoclonal antobodies (mAtb) which impair the binding between checkpoint proteins of T cells and their ligands in cancer cells. The main target for these mAtb is the programmed cell death protein 1 (PD-1) and its ligands, PD-L1 and PD-L2. In this sense, this work propose a quantum biochemistry evaluation of the interactions made by compound thar act in 5-HT1B, PD-1 e GABAB receptors aiming to deepen the knowledge and describe the key points for the docking and stabilization of these compunds within the binding site. Thus, we take into account the crystallographic structure of the three receptors, which were fractionated in amino-acid residues by the molecular fractionation with conjugate caps (MFCC) scheme for posterior quantum (DFT) calculation. By our results, it was possible to predict the relevance of the amino-acids that compose the binding site for the three receptors, including the residues ASP129, ASP352, ASP123, GLU198, ASP204, PHE330, LEU126, PHE351, ILE130, VAL201, VAL200, THR355 e ARG114, that are part of the binding site for dihydroergotamine-5-HTR complex, the residues SER130, GLY151, SER153, HIS170, TYR250, TRP278, GLU349, VAL201, SER152, SER154, GLN348, ARG168 e TRP65, which compose the GABAB’s binding site for GABA, baclofen, SCH50911 and 2-hydroxysaclofen, as well as the lisine residue K131 from PD-1 as the most relevant for the coupling of pembrolizumab, nivolumab and PD-L1. These residues shown the most intense attraction of repulsion energies, forming the key point for the ligand’s anchoring and stabilization. Through these data, it was possible to identify and describe the most important regions for ligands and receptors, as well as explain and differentiate, in a molecular and energetic level, the binding affinity experimentally found for these ligands.

MEMBROS DA BANCA:
Presidente - 6345638 - EUDENILSON LINS DE ALBUQUERQUE
Externo à Instituição - FABIO FERREIRA DE MEDEIROS - UFCG
Externo ao Programa - 2985070 - JONAS IVAN NOBRE OLIVEIRA
Externo à Instituição - JOSE ALZAMIR PEREIRA DA COSTA - UERN
Externo ao Programa - 6346140 - LUCIANO RODRIGUES DA SILVA
Interno - 1352009 - UMBERTO LAINO FULCO