Banca de DEFESA: JÉSSIKA DE OLIVEIRA VIANA

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
STUDENT : JÉSSIKA DE OLIVEIRA VIANA
DATE: 16/06/2023
TIME: 14:00
LOCAL: Google Meet
TITLE:

In silico design, synthesis and activity of spiro-acridine derivatives.

KEY WORDS:

Spiro-acridines, Reverse Virtual Screening, Pteridine Reductase 1, Chitinase, in vitro assay.

PAGES: 114
BIG AREA: Ciências Biológicas
AREA: Biologia Geral
SUMMARY:

Bioactive compounds have been studied in order to offer better efficacy and selectivity against various diseases, representing a promising scenario in drug development. Recently, a series of acridinic derivatives was synthesized and exhibited antileishmanial and anticancer activity. However, the concept of "one target, one drug, one disease" is not always true, as compounds with previously described therapeutic applications can act on more than one target. Based on this, this work aimed to identify, through reverse virtual screening based on the receptor, the probable mechanism of action of spiro-acridinic derivatives. Additionally, the mechanism of action was confirmed through in vitro enzymatic assays. Using these approaches, Chapter I of this work presents the identification, through computational methodologies, of the pteridine reductase 1 (PTR1) enzyme of L. major as a potential target for spiro-acridinic compounds. Additionally, we found the chitinase B1 (CHIB1) enzyme of Aspergillus fumigatus as a potential target against Aspergillosis. For PTR1, docking and molecular dynamics assays presented the high stability of compound 1 in the active site of the enzyme. For CHIB1, other derivatives were subjected to molecular docking and molecular dynamics, identifying 3 compounds with the best profile for the target. In Chapter II, in vitro assays were performed to experimentally confirm the action of spiro-acridinic derivatives on the studied enzymes. For PTR1, in vitro assays demonstrated a KD of 33.1 μM for the best compound, while for chitinase, the best compound showed an IC50 of 0.6 ng/μL. Therefore, this work demonstrated the high efficiency of reverse virtual screening as a target prediction approach. Additionally, the program allowed for characterizing its potency, inhibition modality, and interaction profile with its therapeutic target. Thus, spiro-acridinic derivatives can act as multi-target inhibitors of Leishmania's PTR1 and fungal chitinase.

COMMITTEE MEMBERS:
Externo à Instituição - IGOR JOSÉ DOS SANTOS NASCIMENTO - CESMAC
Externo à Instituição - EDILSON BESERRA DE ALENCAR FILHO - UNIVASF
Presidente - 1893445 - EUZEBIO GUIMARAES BARBOSA
Interno - 1513597 - JOAO PAULO MATOS SANTOS LIMA
Externo ao Programa - 2275890 - MARCELO SOUSA SILVA - null