title: Comparing pharmacophore models derived from crystal structures and from molecular dynamics simulations.
abstract: Pharmacophore modeling is a widely used technique in computer-aided drug discovery. Structure-based pharmacophore models of a ligand in complex with a protein have proven to be useful for supporting in silico hit discovery, hit to lead expansion, and lead optimization. As a structure-based approach it depends on the correct interpretation of ligand-protein interactions. There are legitimate concerns about the fidelity of the bound ligand and about non-physiological contacts with parts of the crystal and the solvent effects that influence the protein structure. A possible way to refine the structure of a protein-ligand system is to use the final structure of a given MD simulation. In this study we compare pharmacophore models built using the initial protein-ligand structure obtained from the protein data bank (PDB) with pharmacophore models built with the final structure of a molecular dynamics simulation. We show that the pharmacophore models differ in feature number and feature type and that the pharmacophore models built from the last structure of a MD simulation shows in some cases better ability to distinguish between active and decoy ligand structures.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Vienna, Austria ; Department of Computational Biological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Marcus
authors.initials: M
authors.lastname: Wieder
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Vienna, Austria ; Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche "STEBICEF", Università di Palermo, Palermo, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Perricone
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seidel
authors.affiliation: Department of Computational Biological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Boresch
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Vienna, Austria.
authors.forename: Thierry
authors.initials: T
authors.lastname: Langer
keywords: Computational chemistry; Molecular dynamics; Molecular modelling; Pharmacophore modelling