title: ProPose: a docking engine based on a fully configurable protein-ligand interaction model.
abstract: Virtual high-throughput screening of molecular databases and in particular high-throughput protein-ligand docking are both common methodologies that identify and enrich hits in the early stages of the drug design process. Current protein-ligand docking algorithms often implement a program-specific model for protein-ligand interaction geometries. However, in order to create a platform for arbitrary queries in molecular databases, a new program is desirable that allows more manual control of the modeling of molecular interactions. For that reason, ProPose, an advanced incremental construction docking engine, is presented here that implements a fast and fully configurable molecular interaction and scoring model. This program uses user-defined, discrete, pharmacophore-like representations of molecular interactions that are transformed on-the-fly into a continuous potential energy surface, allowing for the incorporation of target specific interaction mechanisms into docking protocols in a straightforward manner. A torsion angle library, based on semi-empirical quantum chemistry calculations, is used to provide minimum energy torsion angles for the incremental construction algorithm. Docking results of a diverse set of protein-ligand complexes from the Protein Data Bank demonstrate the feasibility of this new approach. As a result, the seamless integration of pharmacophore-like interaction types into the docking and scoring scheme implemented in ProPose opens new opportunities for efficient, receptor-specific screening protocols. [figure: see text]. ProPose--a fully configurable protein-ligand docking program--transforms pharmacophores into a smooth potential energy surface.
authors.affiliation: markus.seifert@4sc.com
authors.forename: Markus H J
authors.initials: MH
authors.lastname: Seifert
authors.forename: Frank
authors.initials: F
authors.lastname: Schmitt
authors.forename: Thomas
authors.initials: T
authors.lastname: Herz
authors.forename: Bernd
authors.initials: B
authors.lastname: Kramer
mesh_terms: D001665:Binding Sites; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D012984:Software; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011506:Proteins