Format

Send to

Choose Destination
Int J Mol Sci. 2014 Aug 27;15(9):15122-45. doi: 10.3390/ijms150915122.

PL-PatchSurfer: a novel molecular local surface-based method for exploring protein-ligand interactions.

Author information

1
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA. hub@purdue.edu.
2
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA. zhu313@purdue.edu.
3
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA. lmonroe@purdue.edu.
4
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, IN 46285, USA. bures_mark@lilly.com.
5
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA. dkihara@purdue.edu.

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.

PMID:
25167137
PMCID:
PMC4200761
DOI:
10.3390/ijms150915122
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI) Icon for PubMed Central
Loading ...
Support Center