Probing Molecular Docking in a Charged Model Binding Site

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, United States
Journal of Molecular Biology (Impact Factor: 4.33). 05/2006; 357(5):1449-70. DOI: 10.1016/j.jmb.2006.01.034
Source: PubMed


A model binding site was used to investigate charge–charge interactions in molecular docking. This simple site, a small (180 A ˚ 3) engineered cavity in cyctochrome c peroxidase (CCP), is negatively charged and completely buried from solvent, allowing us to explore the balance between electrostatic energy and ligand desolvation energy in a system where many of the common approximations in docking do not apply. A database with about 5300 molecules was docked into this cavity. Retrospective testing with known ligands and decoys showed that overall the balance between electrostatic interaction and desolvation energy was captured. More interesting were prospective docking scre"ens that looked for novel ligands, especially those that might reveal problems with the docking and energy methods. Based on screens of the 5300 compound database, both high-scoring and low-scoring molecules were acquired and tested for binding. Out of 16 new, high-scoring compounds tested, 15 were observed to bind. All of these were small heterocyclic cations. Binding constants

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Available from: Stefan Vetter, Sep 02, 2014
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    • "The compounds were tested for binding by measuring perturbation of the Heme Soret band at 10°C in 100 mM citrate buffer at pH 4.5 or 500 mM MES buffer pH 6.0 [27], [73]. To avoid competition with small cations like potassium, the pH of both buffer conditions was adjusted with Bis-Tris-Propane [27]. "
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