Banca de DEFESA: ESTELA MARIANA GUIMARÃES LOURENÇO

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : ESTELA MARIANA GUIMARÃES LOURENÇO
DATE: 26/03/2020
TIME: 14:30
LOCAL: Sala B416, 3º andar do IMD/UFRN e sala 07 do Instituto de Química da UFMS
TITLE:

Identification of a Selective PDE4B Inhibitor from Bryophyllum pinnatum by Target Fishing Study and In Vitro Evaluation of Quercetin 3-O-α-L-arabinopyranosyl-(1→2)-O-α-L-rhamnopyranoside

KEY WORDS:

Computer aided-drug design, organic synthesis, PDE4B, flavonoids.

PAGES: 117
BIG AREA: Ciências da Saúde
AREA: Farmácia
SUMMARY:

The development of organic synthesis represents an important advance in the discovery of new drugs, being considered an important step in medicinal chemistry. However, the preparation and optimization of drugs is considered a challenge task. The expenditure and time consuming involved in this process are result, particularly, of the prioritization of the synthesis of new compounds without a previously established pharmacological activity. The use of computer aided-drug design using prototypes is considered an important tool, capable to generate guide the synthesis of new molecules. In addition, the prospection of natural products has a long history in drug discovery and is still a source of unprecedented prototypes. Recently, a glycosylated flavonoid with remarkable selectivity for PDE4B isoform in comparison with PDE4A was isolated. This target can be highlighted as a promising alternative for the treatment of diseases as asthma and chronical obstructive pulmonary disease. Nonetheless, the structure of the flavonoid has some structural challenges that prevent it from being considered a potential drug. The present study aims to design and synthesize new potential selective inhibitors of PDE4 enzyme using the newly isolated flavonoid as a prototype. Therefore, a library of selective phosphodiesterase 4B inhibitors was constructed and utilized for the elaboration of a 4D QSAR model and a structure-activity relationship. Molecular dynamics studies and binding free energy calculations were also made to construct hypothesis related to the binding mode of the prototype in the active site of both isoforms. The results demonstrated the importance of polar groups capable to interact with the amino acid residues of M and S pockets. Hydrophobic intermolecular interactions with the phenylalanine present in the Q pocket have been identified as essential, justifying the need of the presence of an aromatic ring or heterocycle in the molecular structure of the inhibitors. The calculated values of binding free energy and the study of protein flexibility allowed the determination of two potential binding modes of the flavonoid in the PDE4A and PDE4B and corroborated with the selectivity observed in vitro. With these informations, analogues that can be obtained by an accessible and versatile synthetic route have been proposed. The compounds have already been obtained from different methodologies that follow the principles of green chemistry. This study may contribute to the obtention of the target compounds and potential new drug prototypes for the treatment of chronic obstructive pulmonary disease and asthma.

BANKING MEMBERS:
Externo à Instituição - EDSON DOS ANJOS DOS SANTOS - UFMS
Externo à Instituição - DÊNIS PIRES DE LIMA - UFMS
Presidente - 1893445 - EUZEBIO GUIMARAES BARBOSA
Interna - 1871916 - RAQUEL BRANDT GIORDANI