title: Exploring the potential of protein-based pharmacophore models in ligand pose prediction and ranking.
abstract: Protein-based pharmacophore models derived from protein binding site atoms without the inclusion of any ligand information have become more popular in virtual screening studies. However, the accuracy of protein-based pharmacophore models for reproducing the critical protein-ligand interactions has never been explicitly assessed. In this study, we used known protein-ligand contacts from a large set of experimentally determined protein-ligand complexes to assess the quality of the protein-based pharmacophores in reproducing these critical contacts. We demonstrate how these contacts can be used to optimize the pharmacophore generation procedure to produce pharmacophore models that optimally cover the known protein-ligand interactions. Finally, we explored the potential of the optimized protein-based pharmacophore models for pose prediction and pose rankings. Our results demonstrate that there are significant variations in the success of protein-based pharmacophore models to reproduce native contacts and consequently native ligand poses dependent on the details of the pharmacophore generation process. We show that the generation of optimized protein-based pharmacophore models is a promising approach for ligand pose prediction and pose rankings.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana 47906, United States.
authors.forename: Bingjie
authors.initials: B
authors.lastname: Hu
authors.forename: Markus A
authors.initials: MA
authors.lastname: Lill
mesh_terms: D001665:Binding Sites; D055808:Drug Discovery / Q000379:methods*; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011506:Proteins