title: Similarity searching in large combinatorial chemistry spaces.
abstract: We present a novel algorithm, called Ftrees-FS, for similarity searching in large chemistry spaces based on dynamic programming. Given a query compound, the algorithm generates sets of compounds from a given chemistry space that are similar to the query. The similarity search is based on the feature tree similarity measure representing molecules by tree structures. This descriptor allows handling combinatorial chemistry spaces as a whole instead of looking at subsets of enumerated compounds. Within few minutes of computing time, the algorithm is able to find the most similar compound in very large spaces as well as sets of compounds at an arbitrary similarity level. In addition, the diversity among the generated compounds can be controlled. A set of 17,000 fragments of known drugs, generated by the RECAP procedure from the World Drug Index, was used as the search chemistry space. These fragments can be combined to more than 10(18) compounds of reasonable size. For validation, known antagonists/inhibitors of several targets including dopamine D4, histamine H1, and COX2 are used as queries. Comparison of the compounds created by Ftrees-FS to other known actives demonstrates the ability of the method to jump between structurally unrelated molecule classes.
authors.affiliation: GMD-German National Research Center for Information Technology, Institute for Algorithms and Scientific Computing, Sankt Augustin. rarey@gmd.de
authors.forename: M
authors.initials: M
authors.lastname: Rarey
authors.forename: M
authors.initials: M
authors.lastname: Stahl
mesh_terms: D000465:Algorithms; D000804:Angiotensin II / Q000037:antagonists & inhibitors; D020650:Combinatorial Chemistry Techniques; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D018491:Dopamine Agonists / Q000737:chemistry / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000737:chemistry; D007527:Isoenzymes / Q000187:drug effects; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D050638:Receptors, Dopamine D4; D015842:Serine Proteinase Inhibitors / Q000737:chemistry
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D018491:Dopamine Agonists; D006634:Histamine H1 Antagonists; D007527:Isoenzymes; D017448:Receptors, Dopamine D2; D015842:Serine Proteinase Inhibitors; D000804:Angiotensin II; D050638:Receptors, Dopamine D4; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases