title: One concept, three implementations of 3D pharmacophore-based virtual screening: distinct coverage of chemical search space.
abstract: Feature-based pharmacophore modeling is a well-established concept to support early stage drug discovery, where large virtual databases are filtered for potential drug candidates. The concept is implemented in popular molecular modeling software, including Catalyst, Phase, and MOE. With these software tools we performed a comparative virtual screening campaign on HSP90 and FXIa, taken from the 'maximum unbiased validation' data set. Despite the straightforward concept that pharmacophores are based on, we observed an unexpectedly high degree of variation among the hit lists obtained. By harmonizing the pharmacophore feature definitions of the investigated approaches, the exclusion volume sphere settings, and the screening parameters, we have derived a rationale for the observed differences, providing insight on the strengths and weaknesses of these algorithms. Application of more than one of these software tools in parallel will result in a widened coverage of chemical space. This is not only rooted in the dissimilarity of feature definitions but also in different algorithmic search strategies.
authors.affiliation: Institute of General, Inorganic, and Theoretical Chemistry, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria. gudrun.spitzer@uibk.ac.at
authors.forename: Gudrun M
authors.initials: GM
authors.lastname: Spitzer
authors.forename: Mathias
authors.initials: M
authors.lastname: Heiss
authors.forename: Martina
authors.initials: M
authors.lastname: Mangold
authors.forename: Patrick
authors.initials: P
authors.lastname: Markt
authors.forename: Johannes
authors.initials: J
authors.lastname: Kirchmair
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolber
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Liedl
mesh_terms: D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry; D008954:Models, Biological; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D004364:Pharmaceutical Preparations