Banca de DEFESA: LEANDRO ROCHA SILVA

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : LEANDRO ROCHA SILVA
DATE: 24/02/2022
TIME: 14:00
LOCAL: Webconferência
TITLE:

Synthesis and antiviral evaluation of potential inhibitors fragmente-based (FBDD) against Dengue and Zika viruses

KEY WORDS:

Flavivirus. Inhibitors, DENV, ZIKV. FBDD

PAGES: 160
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SUMMARY:

Billions of people around the world are infected with debilitating disease-causing pathogens annually. The
most responsible for such diseases are the viruses, among which belonging to the genus Flavivirus deserve
to be highlighted. These belong to the Flaviviridae family, composed of more than 70 viruses, including
Dengue (DENV) and Zika (ZIKV), which are responsible for most infections in humans. It is estimated that 

more than 300 million people are infected with DENV and other items with ZIKV each year. Despite the
alarming number of cases of DENV and ZIKV, as well as their serious consequences in patients, such as
hemorrhagic shock and microcephaly in neonates, respectively; there is no approved effective
pharmacotherapy against both threats. However, there is a vaccine available against DENV, called
Dengvaxia®, which does not offer effective protection against all 5 virus serotypes. DENV and ZIKV share
significant genomic similarity to each other, making it possible to design dual inhibitors against both.
Considering the structural envelope protein (E), essential to mediate the entry / fusion of the virus in the
host cell; and the NS2B-NS3 non-structural protein complex, essential for the processing of the viral
polyprotein during the replication cycle, as well as suppression of the cellular immune response, new
antiviral agents can be designed targeting such macromolecules. Aiming at potential inhibitors of such
targets, we sought to develop a FBDD protocol via molecular docking to screen the best molecular
fragments from an library of fragments. Thus, 254 fragments were designed and optimized (AM1), followed
by molecular docking (Gold®) and (AutoDock Vina®) against the aforementioned proteins. From the
FBDD and adopting the values of 30 (FitScore) and -3.0 kcal / mol (Affinity energy) as a cutoff criterion, 24
promising fragments were selected, composing a set of aldehydes and amines. Then, the most promising
aldehyde, indole-3-carboxaldehyde, was selected for the synthesis of cyanoacrylamides and acrylates,
yielding a set of 165 new molecules, which were again filtered by docking. This step allowed ranking the
best molecules, which had the highest affinity energy values for the targets. Subsequently, several analogs
were synthesized, of which only LRS 25 showed a cytotoxic profile. Compounds LRS01 and LRS02
inhibited 27 and 26% of DENV in enzymatic assay, respectively; LRS05 and LRS08 both had a percentage
of ZIKV inhibition of 25%. Compound LRS04 was able to inhibit ZIKV and DENV by 26 and 25%,
respectively. Therefore, new modifications in LRS04 were carried out in order to potentiate the activity
against the two flaviviruses.

BANKING MEMBERS:
Externo à Instituição - SAMUEL SILVA DA ROCHA PITA - UFBA
Presidente - 3182336 - EDEILDO FERREIRA DA SILVA JUNIOR
Interno - 1369387 - JOAO XAVIER DE ARAUJO JUNIOR
Externa ao Programa - 1461121 - SILVIA HELENA CARDOSO