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Bioorg Med Chem. 2012 Sep 15;20(18):5410-5. doi: 10.1016/j.bmc.2012.03.041. Epub 2012 Mar 24.

New description of protein-ligand interactions using a spherical self-organizing map.

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Chugai Pharmaceutical Company, Kamakura Research Laboratories, Kajiwara 200, Kamakura, Kanagawa 247-8530, Japan.


In a previous report, we studied the mapping ability of the spherical self-organizing map (SSOM). The original 3D structure of the active site of the β2 protein structure was well reproduced by the SSOM. To validate the geometrical transformation and the resulting molecular electrostatic potential (MEP) distribution, the molecular surfaces of 20 β2 ligands were mapped onto the protein SSOM sphere. The MEP values of the two spheres derived from the ligand and the β2 receptor protein were compared. In most cases involving potent ligands, the two spheres had a moderate negative correlation. This indicates that the SSOM approach has excellent potential to represent a complex protein surface as a simple spherical structure. In this study, we perform a quantitative structure-activity relationship (QSAR) study of caspase-3 inhibitors based on the SSOM technique. Initially, the active site of the protein structure 'caspase-3' was characterized by the SSOM using the MEP values. Each inhibitor was then projected onto the protein SSOM sphere and the chemical descriptors were derived from the ligand SSOM sphere. The correlation of the chemical descriptors and the inhibitory activities was investigated using the support vector regression (SVR) method. Finally, the important MEP descriptors from the final SVR model were examined. The structural requirements of caspase-3 inhibitors are discussed from the perspectives of both the ligand and protein structures.

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