Docking, qm/mm, and molecular dynamics simulations of the hexose transporter from plasmodium falciparum (pfht)
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Universidade Federal de Minas Gerais
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Artigo de periódico
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Membros da banca
Resumo
Malaria is the most prevalent parasitic disease in the world. Currently, an effective vaccine for malaria does
not exist, and chemotherapy must be used to treat the disease. Because of increasing resistance to current
antimalarial drugs, new treatments must be developed. Among the many potential molecular targets, the
hexose transporter of Plasmodium falciparum (PfHT) is particularly promising because it plays a vital role
in glucose transport for the parasite. Thus, this study aims to determine the three-dimensional structure of
PfHT and to describe the intermolecular interactions between active glycoside derivatives and PfHT. Such
information should aid in the development of new antimalarial drugs. The receptor PfHT was constructed
from primary sequences deposited in the SWISS MODEL database. Next, molecular docking simulations
between O-(undec-10-en)-l-D-glucose and the constructed active site models were performed using
Autodock Vina. The glycoside derivative-PfHT complexes were then refined using the hybrid QM/MM
(PM3/ff03) method within the AMBER package. The models were then evaluated using Ramachandran
plots, which indicated that 93.2% of the residues in the refined PfHT models (P5) were present in favorable
regions. Furthermore, graphical plots using ANOLEA showed that the potential energies of interaction for
atoms unbonded to P5 were negative. Finally, the O-(undec-10-en)-l-D-glucose-PfHT complex was eval-
uated using 20-ns Molecular Dynamics simulations with an ff03 force field. Docking and QM/MM studies
revealed the amino acids essential for molecular recognition of and activity on glycosides. Inhibition of
glucose transporters may prevent the development and metabolism of P. falciparum, so a description of
the receptor’s structure is a critical step towards rational drug design.
Abstract
Assunto
Glicose, Malária
Palavras-chave
Comparative homology modeling, Computer aided drug-design (CADD), Glucose transport, Malaria, PfHT, QM/MM
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Endereço externo
https://www.sciencedirect.com/science/article/pii/S1093326316300493