Pharmacophore Alignment Search Tool (PhAST): Significance Assessment of Chemical Similarity
Article first published online: 13 JUN 2013
Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Volume 32, Issue 7, pages 625–646, July 2013
How to Cite
Hähnke, V., Rupp, M., Hartmann, A. K. and Schneider, G. (2013), Pharmacophore Alignment Search Tool (PhAST): Significance Assessment of Chemical Similarity. Mol. Inf., 32: 625–646. doi: 10.1002/minf.201300021
- Issue published online: 12 JUL 2013
- Article first published online: 13 JUN 2013
- Manuscript Accepted: 19 APR 2013
- Manuscript Received: 12 FEB 2013
- EU Marie Curie. Grant Number: No. 273039
- Chemical Computing Group Inc.
- Chemical similarity;
- Sequence alignment;
- Virtual screening
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/.