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Building Hypotheses and Searching Databases Two ways of creating an hypothesis • Automatically create a chemical featurebased hypothesis from a set of compounds with respect to a type of activity. • Build an hypothesis by assembling substructures and chemical functions and specifying the geometric constraints between them. Components of an Hypothesis • Assemble the components from known data such as the atomic coordinates available from X-ray crystallographic data. • Express the characteristics of the hypothesis as a collection of particular chemical substructures or a collection of chemical functions such as hydrogen bond donors and hydrophilic groups, or a combination of substructures and chemical functions. Chemical Substructures Available • The feature dictionary contains a large library of chemical functional groups such as primary, secondary, tertiary amines, hydroxyl, carbonyl, acridyl, acetoamido, 1-beta-glucopyranosyl, amino acids etc, etc. Chemical Functions Available • The chemical functions available include HB ACCEPTOR, HB ACCEPTOR lipid, HB DONOR, HYDROPHOBIC, HYDROPHOBIC aliphatic, HYDROPHOBIC aromatic, NEG CHARGE, NEG IONIZABLE, POS CHARGE, POS IONIZABLE, RING AROMATIC Chemical Functions Available • The distances, angles, and/or torsions between items in an hypothesis, the preferred location of a chemical feature, and a range of elements per atom position may be specified within the hypothesis or a substructure of the hypothesis. • Excluded volumes may also be specified. Using the hypothesis? • Having built the hypothesis databases may then be searched with the hypothesis to find compounds within the databases that match the hypothesis. Building a Substructure Hypotheses and Searching Databases Hydrogen count set to “anything” Specifying atom range per atom position Specifying atom range per atom position Searching a Database with an Hypothesis • Once the hypothesis has been designed and built it may be used to search a database for compounds that contain the defined features. Results of Database search. Default 300 hits. Hit example 1 Hit example 1 Compound data Compound sort. Handling large datasets. Compound property report. Managing Databases: Coping with extremely large numbers. • Are scientists going to manage in the new world without an in depth knowledge of mathematics and statistics? • Are we training scientists to cope with tools such as, cluster analysis, discriminate analysis, cross validation techniques, neural networks, Fourier transformations etc, etc. • Do we need courses in the design, building and interrogation of databases. Building a Feature Based Hypotheses and Searching Databases Setting distance constraints. Setting distance constraints. Hybrid hypothesis of chemical functions and fragments. Using the generic b-adrenergic agonist to search a database. Databases? • • • • • Global structural databases e.g. CCSD Structure specific databases. Therapeutic area based databases. Multi-conformer databases. Composite databases that encapsulate the information of multi-gigabyte files. • QSAR based databases. • Commercially available versus problem specific databases.