Journal
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
Volume 5, Issue 9, Pages 2565-2573Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ct900257t
Keywords
-
Funding
- Government of Catalonia [BP-A 2007]
- IIT
Ask authors/readers for more resources
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 (K-d = 3.9 mu M, corresponding to AGO = -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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available