Banca de QUALIFICAÇÃO: LÍVIA CAROLINA ANDRADE FIGUEIRÊDO

Uma banca de QUALIFICAÇÃO de MESTRADO foi cadastrada pelo programa.
STUDENT : LÍVIA CAROLINA ANDRADE FIGUEIRÊDO
DATE: 16/04/2024
TIME: 09:00
LOCAL: Videoconferência
TITLE:

IN SILIC PROSPECTING OF POTENTIAL THERAPEUTIC COMPOUNDS FOR LEISHMANIASIS AND IN VITRO EVALUATION OF THE ANTILEISHMANIA ACTIVITY OF THE SELECTED SYNTHETIC COMPOUNDS


KEY WORDS:
Leishmania. Antileishmania Activity. Molecular Docking.

PAGES: 63
BIG AREA: Ciências da Saúde
AREA: Medicina
SUMMARY:
Leishmaniases, diseases caused by parasites of the genus Leishmania, represent a significant
health challenge in various regions. Therefore, this research addressed this issue through an
innovative approach, combining in silico and in vitro methods to evaluate promising synthetic
compounds in combating leishmaniases. Leishmaniases, being considered neglected diseases,
demand continuous search for new treatments, especially due to the development of resistance
to existing drugs. In this context, the search for therapeutic compounds through in silico
approaches is a promising strategy, allowing efficient screening of candidate molecules before
in vitro assays. This study aimed to identify and analyze, by structural bioinformatics methods,
protein structures of Leishmania braziliensis, Leishmania amazonensis, and Leishmania
infantum species whose binding sites interact with chemical compounds ZINC9829539 and
ZINC4270223. Additionally, it proposed to evaluate the in vitro antileishmanial activity of
these compounds on intracellular amastigote forms in standard cultures of the three species.
The methodology was divided into two stages: an in silico study and an in vitro study. In the in
silico study, molecular docking based on target and ligand was performed, as well as reverse
docking to explore new targets. In the in vitro stage, compound cytotoxicity assays were
conducted using the THP-1 cell model and macrophages infected with different Leishmania
species. The synthetic compounds ZINC9829539 and ZINC4270223 were evaluated. In the in
silico study, it was observed that ZINC9829539 showed a higher ChemPLP score than the
crystallographic ligand for three targets (4AGS, 4AIR, and 3GZ3) compared to the lowest
RMSD, indicating significant affinity with these enzymes, while ZINC4270223 obtained a
higher score only in relation to the 4AGS target compared to the lowest RMSD. In the in vitro
study with THP-1 cells, it was noted that the compounds have relatively high CC50, indicating
low toxicity to host cells. Both compounds showed inhibitory activity against the three
Leishmania strains tested, with IC50 values ranging from 10.4 to 28 µM. The IC50 values of
the positive control (Amphotericin B) were in the range of 0.02 to 0.075 µM. Both compounds
show a selectivity index (SI) between 0.57 and 2.66, values considered moderate. In summary,
the data suggest that synthetic compounds ZINC9829539 and ZINC4270223 showed moderate
antileishmanial activity, with relatively low toxicity to host cells. However, the potency of these
compounds is still below that of the positive control, Amphotericin B. This indicates that there
is room to improve the selectivity of the compounds to make them more effective in treating
leishmaniases.

BANKING MEMBERS:
Interno - 1544480 - EDUARDO SERGIO DA SILVA
Externo à Instituição - FRANCO HENRIQUE ANDRADE LEITE - UEFS
Presidente - 1084423 - RAFAEL GONCALVES TEIXEIRA NETO
Notícia cadastrada em: 27/03/2024 09:40
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