title: Significance estimation for sequence-based chemical similarity searching (PhAST) and application to AuroraA kinase inhibitors.
abstract: BACKGROUND
  Chemical similarity searching allows the retrieval of preferred screening molecules from a compound database. Candidates are ranked according to their similarity to a reference compound (query). Assessing the statistical significance of chemical similarity scores helps prioritizing significant hits, and identifying cases where the database does not contain any promising compounds.
  
  
  METHODS
  Our text-based similarity measure, Pharmacophore Alignment Search Tool (PhAST), employs pair-wise sequence alignment. We adapted the concept of E-values as significance estimates and employed a sampling technique that incorporates the principle of importance sampling in a Markov chain Monte Carlo simulation to generate distributions of random alignment scores. These distributions were used to compute significance estimates for similarity scores in a preliminary prospective virtual screen for inhibitors of Aurora A kinase.
  
  
  CONCLUSIONS
  Assessing the significance of compound similarity computed with PhAST allows for a statistically motivated identification of candidate screening compounds. Inhibitors of Aurora A kinase were retrieved from a large compound library.
authors.affiliation: Swiss Federal Institute of Technology, Department of Chemistry & Applied Biosciences, 8093 Zürich, Switzerland.
authors.forename: Volker
authors.initials: V
authors.lastname: Hähnke
authors.forename: Nickolay
authors.initials: N
authors.lastname: Todoroff
authors.forename: Tiago
authors.initials: T
authors.lastname: Rodrigues
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D064127:Aurora Kinases; D020650:Combinatorial Chemistry Techniques; D062126:Databases, Chemical; D006801:Humans; D009010:Monte Carlo Method; D010879:Piperazines / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012984:Software; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D064127:Aurora Kinases; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines