Banca de QUALIFICAÇÃO: ARANTHYA HEVELLY DE LIMA COSTA

Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.
STUDENT : ARANTHYA HEVELLY DE LIMA COSTA
DATE: 14/09/2023
TIME: 09:00
LOCAL: Videoconferencia
TITLE:

Biochemical analysis of protein-ligand interactions between DHODH and TyrRS enzymes of Plasmodium falciparum.

KEY WORDS:

dihydroorotate dehydrogenase, tyrosine-tRNA synthetase, interaction energies, MFCC and DFT.

PAGES: 101
BIG AREA: Ciências Biológicas
AREA: Bioquímica
SUMMARY:

Malaria is a parasitic disease caused by unicellular protozoa of the genus Plasmodium and
occurs in more than 90 countries, with most cases on the African and Asian continents. The use
of antimalarial drugs is critical for both treatment and prevention of the disease. However,
parasites have begun to develop resistance to antimalarial drugs due in part to improper use and
inadequate exposure, rendering current therapies ineffective. Therefore, new therapeutic
approaches are needed to overcome parasite drug resistance and increase the efficacy of drug
therapy against the disease. The goal of this research is to characterize the relationships that
determine the behavior of the protein-ligand complexes of the enzymes dihydroorotate
dehydrogenase (DHODH) and tyrosine-tRNA synthetase (TyrRS) from Plasmodium
falciparum. In addition, the energy levels of these complexes will be presented in wild-type
PfDHODH systems in which the DSM483, DSM557, and DSM1 ligands are present and in
PfDHODH with the C276F mutation together with DMS1. Similarly, the PfTyrRS enzyme was
also studied both in its wild-type form bound to ML901-Tyr and AMS-Tyr and with the S234C
mutation, again bound to ML901-Tyr. Using the method of Molecular Fractionation with
Conjugate Caps (MFCC), amino acid residues were partitioned to calculate individual
interactions using the formalism DFT (Functional Density Theory). The study with PfDHODH
enzyme revealed that amino acid residues Arg265, Cys184 and Phe188 were crucial for the
interactions and exhibited significant interaction energies with the four complexes studied.
Moreover, the energy value of the DSM1 inhibitor was not affected by the structural changes
caused by the C276F mutation, demonstrating its ability to bind to the enzyme. In studying the
work with PfTyrRS, six important residues were found to be common to the three complexes.
These residues include Asp61, Gln73, Gln192, Gln210, Met237, and Phe63, most of which play
essential roles in ATP binding. This discovery provides a comprehensive understanding of the
interaction between PfDHODH and PfTyrRS enzymes and their inhibitors. The information
gathered in this study is proving to be relevant for the development of new drug therapies and
could serve as an aid in the discovery of new, more sophisticated and effective antimalarial
drugs.

COMMITTEE MEMBERS:
Presidente - 2412258 - EDILSON DANTAS DA SILVA JUNIOR
Externo à Instituição - JOSÉ XAVIER DE LIMA NETO
Externa à Instituição - KATYANNA SALES BEZERRA