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
Interno - 1352009 - UMBERTO LAINO FULCO
Interno - 1720860 - VANESSA DE PAULA SOARES RACHETTI
Externo ao Programa - 2985070 - JONAS IVAN NOBRE OLIVEIRA
Externo ao Programa - 6346140 - LUCIANO RODRIGUES DA SILVA
Externo à Instituição - JOSE ALZAMIR PEREIRA DA COSTA - UERN
Externo à Instituição - FABIO FERREIRA DE MEDEIROS - UFCG