title: PL-PatchSurfer: a novel molecular local surface-based method for exploring protein-ligand interactions.
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.
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA. hub@purdue.edu.
authors.forename: Bingjie
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA. zhu313@purdue.edu.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA. lmonroe@purdue.edu.
authors.forename: Lyman
authors.initials: L
authors.lastname: Monroe
authors.affiliation: Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, IN 46285, USA. bures_mark@lilly.com.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Bures
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA. dkihara@purdue.edu.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kihara
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D008024:Ligands; D062105:Molecular Docking Simulation / Q000379:methods*; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D008024:Ligands; D011506:Proteins; D054852:Small Molecule Libraries