title: Pharmacophore Alignment Search Tool (PhAST): Significance Assessment of Chemical Similarity.
abstract: Previously, we proposed a ligand-based virtual screening technique (PhAST) based on global alignment of linearized interaction patterns. Here, we applied techniques developed for similarity assessment in local sequence alignments to our method resulting in p-values for chemical similarity. We compared two sampling strategies, a simple sampling strategy and a Markov Chain Monte Carlo (MCMC) method, and investigated the similarity of sampled distributions to Gaussian, Gumbel, modified Gumbel, and Gamma distributions. The Gumbel distribution with a Gaussian correction term was identified as the most similar to the observed empirical distributions. These techniques were applied in retrospective screenings on a drug-like dataset. Obtained p-values were adjusted to the size of the screening library with four different methods. Evaluation of E-value thresholds corroborated the Bonferroni correction as a preferred means to identify significant chemical similarity with PhAST. An online version of PhAST with significance estimation is available at http://modlab-cadd.ethz.ch/.
authors.affiliation: Eidgenössische Technische Hochschule (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland phone: +1 (202)436-5989. volker@cheminformatics.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Hähnke
authors.affiliation: Eidgenössische Technische Hochschule (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland phone: +1 (202)436-5989.
authors.forename: Matthias
authors.initials: M
authors.lastname: Rupp
authors.affiliation: Universität Oldenburg, Computational Theoretical Physics, Institut für Physik, Carl-von-Ossietzky Strasse 9-11, 26111 Oldenburg, Germany.
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Hartmann
authors.affiliation: Eidgenössische Technische Hochschule (ETH), Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland phone: +1 (202)436-5989.
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
keywords: Chemical similarity; Pharmacophore; Sequence alignment; Significance; Virtual screening