Docking ligands on protein surfaces: The case study of prion protein

Agata Kranjc, Salvatore Bongarzone, Giulia Rossetti, Xevi Biarnés, Andrea Cavalli, Maria Laura Bolognesi, Marinella Roberti, Giuseppe Legname, Paolo Carloni

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33 Cites (Scopus)


Molecular docking of ligands targeting proteins undergoing fibrillization in neurodegenerative diseases is difficult because of the lack of deep binding sites. Here we extend standard docking methods with free energy simulations in explicit solvent to address this issue in the context of the prion protein surface. We focus on a specific ligand (2-pyrrolidin-1-yl-N-[4-[4-(2-pyrrolidin-1-yl-acetylamino)-benzyl]-phenyl]-acetamide), which binds to the structured part of the protein as shown by NMR (Kuwata, K. et al. Proc Natl Acad Sci U.S.A. 2007, 104, 11921-11926). The calculated free energy of dissociation (7.8 (0.9 kcal/mol) is in good agreement with the value derived by the experimental dissociation constant (Kd) 3.9 μM, corresponding to ΔG0) -7.5 kcal/mol). Several binding poses are predicted, including the one reported previously. Our prediction is fully consistent with the presence of multiple binding sites, emerging from NMR measurements. Our molecular simulation-based approach emerges, therefore, as a useful tool to predict poses and affinities of ligand binding to protein surfaces.

Idioma originalAnglès
Pàgines (de-a)2565-2573
Nombre de pàgines9
RevistaJournal of Chemical Theory and Computation
Estat de la publicacióPublicada - de set. 2009
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