Banca de QUALIFICAÇÃO: LEANDRO ROCHA SILVA

Uma banca de QUALIFICAÇÃO de MESTRADO foi cadastrada pelo programa.
STUDENT : LEANDRO ROCHA SILVA
DATE: 26/08/2021
TIME: 09:00
LOCAL: Google Meet
TITLE:

Synthesis and Antiviral Evaluation of Fragment-Based Inhibitors Against Flaviviruses

KEY WORDS:

Flavivirus. Inhibitors, DENV, ZIKV. FBDD

PAGES: 120
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 4 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 analogues were synthesized and are undergoing biological tests to confirm the in silico results. However, the derivatives already obtained and characterized did not show a cytotoxic profile. The results achieved so far show that the protocol used is quite efficient and effective for the discovery of new bioactive molecules.

BANKING MEMBERS:
Presidente - 3182336 - EDEILDO FERREIRA DA SILVA JUNIOR
Externo ao Programa - 1612086 - ENIO JOSE BASSI
Externa ao Programa - 1461121 - SILVIA HELENA CARDOSO
Interno - 1366289 - THIAGO MENDONCA DE AQUINO