TY - JOUR
T1 - Docking ligands on protein surfaces
T2 - The case study of prion protein
AU - Kranjc, Agata
AU - Bongarzone, Salvatore
AU - Rossetti, Giulia
AU - Biarnés, Xevi
AU - Cavalli, Andrea
AU - Bolognesi, Maria Laura
AU - Roberti, Marinella
AU - Legname, Giuseppe
AU - Carloni, Paolo
PY - 2009/9
Y1 - 2009/9
N2 - 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.
AB - 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.
KW - Molecular-dynamics method
KW - Particle mesh ewald
KW - Drug design
KW - Neurodegenerative diseases
KW - Conformational energies
KW - Genetic algorithm
KW - Flexible docking
KW - Nmr structure
KW - Resp model
KW - Simulations
UR - http://www.scopus.com/inward/record.url?scp=73349104647&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=pure_univeritat_ramon_llull&SrcAuth=WosAPI&KeyUT=WOS:000269488300034&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1021/ct900257t
DO - 10.1021/ct900257t
M3 - Article
C2 - 26616631
AN - SCOPUS:73349104647
SN - 1549-9618
VL - 5
SP - 2565
EP - 2573
JO - Journal of Chemical Theory and Computation
JF - Journal of Chemical Theory and Computation
IS - 9
ER -