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Kranjc A, Bongarzone S, Rossetti G, et al. Docking Ligands on Protein Surfaces: The Case Study of Prion Protein. J Chem Theory Comput. 2009;5(9):2565-73doi: 10.1021/ct900257t.
Kranjc, A., Bongarzone, S., Rossetti, G., Biarnés, X., Cavalli, A., Bolognesi, M. L., Roberti, M., Legname, G., & Carloni, P. (2009). Docking Ligands on Protein Surfaces: The Case Study of Prion Protein. Journal of chemical theory and computation, 5(9), 2565-73. https://doi.org/10.1021/ct900257t
Kranjc, Agata, et al. "Docking Ligands on Protein Surfaces: The Case Study of Prion Protein." Journal of chemical theory and computation vol. 5,9 (2009): 2565-73. doi: https://doi.org/10.1021/ct900257t
Kranjc A, Bongarzone S, Rossetti G, Biarnés X, Cavalli A, Bolognesi ML, Roberti M, Legname G, Carloni P. Docking Ligands on Protein Surfaces: The Case Study of Prion Protein. J Chem Theory Comput. 2009 Sep 08;5(9):2565-73. doi: 10.1021/ct900257t. Epub 2009 Aug 14. PMID: 26616631.
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J Chem Theory Comput. 2009 Sep 08;5(9):2565-73. doi: 10.1021/ct900257t. Epub 2009 Aug 14.

Docking Ligands on Protein Surfaces: The Case Study of Prion Protein.

Journal of chemical theory and computation

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

Affiliations

  1. Statistical and Biological Physics Sector, Neurobiology Sector, International School for Advanced Studies (SISSA), SISSA-Unit, Italian Institute of Technology, 34014 Trieste, Italy, Department of Pharmaceutical Sciences, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy, Department of Drug Discovery and Development, Italian Institute of Technology, 16163 Genova, Italy, and CNR-INFM-DEMOCRITOS Modeling Center for Research in Atomistic Simulation, 34014 Trieste, Italy.

PMID: 26616631 DOI: 10.1021/ct900257t

Abstract

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 ΔG(0) = -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.

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