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Int. J. Mol. Sci. 2014, 15(9), 15122-15145; https://doi.org/10.3390/ijms150915122

PL-PatchSurfer: A Novel Molecular Local Surface-Based Method for Exploring Protein-Ligand Interactions

1
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
2
Department of Computer Science, Purdue University, West Lafayette, IN 47907, USA
3
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, IN 46285, USA
*
Author to whom correspondence should be addressed.
Received: 24 April 2014 / Revised: 30 July 2014 / Accepted: 12 August 2014 / Published: 27 August 2014
(This article belongs to the Collection Proteins and Protein-Ligand Interactions)
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Abstract

Structure-based computational methods have been widely used in exploring protein-ligand interactions, including predicting the binding ligands of a given protein based on their structural complementarity. Compared to other protein and ligand representations, the advantages of a surface representation include reduced sensitivity to subtle changes in the pocket and ligand conformation and fast search speed. Here we developed a novel method named PL-PatchSurfer (Protein-Ligand PatchSurfer). PL-PatchSurfer represents the protein binding pocket and the ligand molecular surface as a combination of segmented surface patches. Each patch is characterized by its geometrical shape and the electrostatic potential, which are represented using the 3D Zernike descriptor (3DZD). We first tested PL-PatchSurfer on binding ligand prediction and found it outperformed the pocket-similarity based ligand prediction program. We then optimized the search algorithm of PL-PatchSurfer using the PDBbind dataset. Finally, we explored the utility of applying PL-PatchSurfer to a larger and more diverse dataset and showed that PL-PatchSurfer was able to provide a high early enrichment for most of the targets. To the best of our knowledge, PL-PatchSurfer is the first surface patch-based method that treats ligand complementarity at protein binding sites. We believe that using a surface patch approach to better understand protein-ligand interactions has the potential to significantly enhance the design of new ligands for a wide array of drug-targets. View Full-Text
Keywords: PL-PatchSurfer; surface patch; ligand prediction; virtual screening; 3D Zernike descriptor PL-PatchSurfer; surface patch; ligand prediction; virtual screening; 3D Zernike descriptor
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Hu, B.; Zhu, X.; Monroe, L.; Bures, M.G.; Kihara, D. PL-PatchSurfer: A Novel Molecular Local Surface-Based Method for Exploring Protein-Ligand Interactions. Int. J. Mol. Sci. 2014, 15, 15122-15145.

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