Università degli Studi di Milano

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Presentation transcript:

Università degli Studi di Milano Facoltà di Farmacia Modelling the folding of transmembrane proteins using a novel fragmental approach: the human ghrelin receptor and the glutamate transporter EAAT1 Alessandro Pedretti & Giulio Vistoli

The fragmental approach1 Aminoacid sequence of the transmembrane protein Fragmentation in structural domains Folding prediction of each fragment Assembling using a global template

Global template

Ligand-protein complexes The fragmental approach2 Side chains building Rough model Final model MM/MD refinement Molecular docking Ligand-protein complexes Lignads Model validation

Spiroindane derivative HGHS-R1a ligand binding sites Glu 124 Polar Arg 283 Apolar Spiroindane derivative EC50 = 0.6 nM TM3 TM6

pEC50 = 6.06 (0.35) – 0.070 (0.01) x Scorepol QSAR analysis pEC50 = 6.06 (0.35) – 0.070 (0.01) x Scorepol n = 35; r2 = 0.57; q2 = 0.51 s = 0.29; F = 44.30 Scorepol (Kcal/mol) pEC50 pEC50 = 5.96 (0.29) – 0.068 (0.0087) Scorepol – 0.014 (0.0033) Scoreapol n = 35; r2 = 0.72; q2 = 0.67; s = 0.24; F = 42.06 pEC50 calculated pEC50 experimental

Conclusions The fragmental approach allows to obtain good models avoiding the construction of bovine rhodopsin clones. The computational results are confirmed by the good correlation between the experimental data and the docking scores. The method was successfully applied to the non-GPCR protein EAAT1, obtaining results confirmed by the experimental data.