Fragmental modeling of hPepT2 and analysis of its binding features by docking studies and pharmacophore mapping.

Article Details

Citation

Pedretti A, De Luca L, Marconi C, Regazzoni L, Aldini G, Vistoli G

Fragmental modeling of hPepT2 and analysis of its binding features by docking studies and pharmacophore mapping.

Bioorg Med Chem. 2011 Aug 1;19(15):4544-51. doi: 10.1016/j.bmc.2011.06.027. Epub 2011 Jun 16.

PubMed ID
21741846 [ View in PubMed
]
Abstract

Over the last years, considerable progress has been made for the identification and characterization of drug transporters, and several modeling studies have been undertaken to predict their effects on ADME profiling. Thus, this study was focused on the peptide transporter hPepT2, which influences the regional pharmacokinetics in brain, the reabsorption from renal tubular fluid and the pulmonary delivery. A reliable model for hPepT2 was generated by fragments based on the resolved structure of the homologue lactose permease LacY and the structure is made available as Supplementary data. The interaction capacities of such a model were explored by docking a set of 75 known ligands. Docking results underlined the predilection of hPepT2 for highly hydrophobic ligands and the key role of ionic interactions elicited by both charged termini. The docking results were further verified developing a pharmacophore model which clarified the key features required for an optimal hPepT2 affinity and confirmed the main factors governing the hPepT2/hPepT1 selectivity. The soundness of the docking results and the agreement with the pharmacophore mapping afford an encouraging validation for the proposed hPepT2 model and suggest that it can be conveniently exploited to design peptide-like molecules with an improved affinity for this transporter.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
AmpicillinSolute carrier family 15 member 2ProteinHumans
Unknown
Not AvailableDetails
BenzylpenicillinSolute carrier family 15 member 2ProteinHumans
Unknown
Inhibitor
Details
CefotaximeSolute carrier family 15 member 2ProteinHumans
Unknown
Not AvailableDetails
OxacillinSolute carrier family 15 member 2ProteinHumans
Unknown
Not AvailableDetails
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AmoxicillinSolute carrier family 15 member 2Ki (nM)430000N/AN/ADetails
AmpicillinSolute carrier family 15 member 2Ki (nM)1300000N/AN/ADetails
BenzylpenicillinSolute carrier family 15 member 2Ki (nM)11000000N/AN/ADetails
CefaclorSolute carrier family 15 member 2Ki (nM)29000N/AN/ADetails
CefadroxilSolute carrier family 15 member 2Ki (nM)3000N/AN/ADetails
CefalotinSolute carrier family 15 member 2Ki (nM)8300000N/AN/ADetails
CefepimeSolute carrier family 15 member 2Ki (nM)11000000N/AN/ADetails
CefiximeSolute carrier family 15 member 2Ki (nM)2600000N/AN/ADetails
CefmetazoleSolute carrier family 15 member 2Ki (nM)4300000N/AN/ADetails
CefotaximeSolute carrier family 15 member 2Ki (nM)20000000N/AN/ADetails
CefuroximeSolute carrier family 15 member 2Ki (nM)12589254N/AN/ADetails
CefuroximeSolute carrier family 15 member 2Ki (nM)12600000N/AN/ADetails
CephalexinSolute carrier family 15 member 2Ki (nM)75000N/AN/ADetails
CloxacillinSolute carrier family 15 member 2Ki (nM)950000N/AN/ADetails
CyclacillinSolute carrier family 15 member 2Ki (nM)44000N/AN/ADetails
DicloxacillinSolute carrier family 15 member 2Ki (nM)420000N/AN/ADetails
OxacillinSolute carrier family 15 member 2Ki (nM)3300000N/AN/ADetails