Steric multiplet fingerprints as screens in high-throughput screening

CINF 83

Essam Metwally1, Robert Clark2, and Peter C. Fox1. (1) Tripos Inc, 1699 South Hanley Road, Saint Louis, MO 63144, (2) Discovery Software, Tripos Inc, 1699 South Hanley Road, St. Louis, MO 63144
Rapid screening of large chemical databases for potential lead compounds has become ever more important as the number of known biological targets has risen dramatically. Using fully flexible 3d searching on a large database is prohibitively time consuming to be routinely used as a screening method, thus a rapid screen that allows the majority of compounds to be filtered out before a 3d search is run is highly desirable. A number of methods have been developed to rapidly screen databases utilizing fragment-based fingerprints, and more recently pharmacophoric feature based fingerprints. The steric or shape component of each molecule is disregarded in these types of fingerprints. Screening on a fingerprint descriptor that encodes the shape information of a query may be a valuable addition to the fragment or pharmacophore-based screens.

We have extended Tripos' tuplet technology to include the ability to use steric multiplet fingerprints, which encode flexible shape information of the database molecules, either alone or in concert with pharmacophoric feature multiplets. The definition, creation and storage methodologies for these fingerprints will be discussed. Examples of the use of these fingerprints as database screens will also be covered.