Paper Citing NAMD - Abstract
Pedretti, Alessandro; De Luca, Laura; Sciarrillo, Cristina; Vistoli, Giulio
Fragmental modeling of human glutamate transporter EAAT1 and analysis of its binding modes by docking and pharmacophore mapping
CHEMMEDCHEM, 3:79-90, JAN 2008
The objective of the study was to generate a reliable model of the homotrimeric structure for the human glutamate transporter EAAT1, based on experimental folding of transporter homologue from Pyrococcus horikoshii. The monomer structure was derived using a fragmental approach and the homotrimer was assembled using protein-protein docking. The interaction capacities of the EAAT1 model were explored by docking a set of 32 known ligands including both substrates and blockers. Docking results unveiled that the substrates' bioactivity is strongly influenced by a,precise fitting between the ligand and the EAAT1 binding site, wheras the blockers' activity depends on a set of apolar contacts that ligands can realize in an adjacent hydrophobic subpocket. The docking results were further verified by generating two pharmacophore models (the first for substrates and the latter for blockers) which revealed the features necessary for high EAAT1 activity. The consistency of docking results and the agreement with pharmacophore models afford an encouraging validation for the EAAT1 model and emphasize the soundness of the fragmental approach to model any transmembrane protein.
