title: Docking, QM/MM, and molecular dynamics simulations of the hexose transporter from Plasmodium falciparum (PfHT).
abstract: 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 evaluated 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.
authors.affiliation: Núcleo de Pesquisa em Química Biológica, Universidade Federal de São João del-Rei, Divinópolis, MG, Brazil; Laboratório de Modelagem Molecular, Universidade Federal de São João del-Rei, Divinópolis, MG, Brazil; Laboratório de Química Medicinal Farmacêutica, Universidade Federal de São João del-Rei, Divinópolis, MG, Brazil.
authors.forename: Amanda Luisa da
authors.initials: AL
authors.lastname: Fonseca
authors.affiliation: Laboratório de Química Medicinal Farmacêutica, Universidade Federal de São João del-Rei, Divinópolis, MG, Brazil.
authors.forename: Renata Rachide
authors.initials: RR
authors.lastname: Nunes
authors.affiliation: Laboratório de Química Medicinal Farmacêutica, Universidade Federal de São João del-Rei, Divinópolis, MG, Brazil.
authors.forename: Vanildo Martins Lima
authors.initials: VM
authors.lastname: Braga
authors.affiliation: Laboratório de Modelagem Molecular, Universidade Federal de São João del-Rei, Divinópolis, MG, Brazil.
authors.forename: Moacyr
authors.initials: M
authors.lastname: Comar
authors.affiliation: Laboratório de Química, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Alves
authors.affiliation: Núcleo de Pesquisa em Química Biológica, Universidade Federal de São João del-Rei, Divinópolis, MG, Brazil.
authors.forename: Fernando de Pilla
authors.initials: Fde P
authors.lastname: Varotti
authors.affiliation: Laboratório de Química Medicinal Farmacêutica, Universidade Federal de São João del-Rei, Divinópolis, MG, Brazil. Electronic address: labqf_ufsj@ufsj.edu.br.
authors.forename: Alex Gutterres
authors.initials: AG
authors.lastname: Taranto
mesh_terms: D000962:Antimalarials / Q000737:chemistry* / Q000627:therapeutic use; D015195:Drug Design; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D017780:Malaria Vaccines / Q000737:chemistry / Q000627:therapeutic use; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000472:pathogenicity; D011487:Protein Conformation
chemical_list: D000962:Antimalarials; D017780:Malaria Vaccines; D009004:Monosaccharide Transport Proteins; D005947:Glucose
keywords: Comparative homology modeling; Computer aided drug-design (CADD); Glucose transport; Malaria; PfHT; QM/MM