Planejamento assistido por computador e síntese de potenciais inibidores seletivos de PDE4 baseados em produtos naturais
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 pro...
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| Formato: | Dissertação |
| Idioma: | pt_BR |
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Universidade Federal do Rio Grande do Norte
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| Endereço do item: | https://repositorio.ufrn.br/jspui/handle/123456789/29961 |
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| Resumo: | 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 deeper molecular studies. 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 quercetin 3-O-α-L-arabinopyranosyl-(1→2)-O-α-L-rhamnopyranoside 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 structureactivity 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. |
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