Comments on the design of chemical libraries for screening
Hugo O. Villar
Telik, Inc., Discovery Technologies Division, 750 Gateway Blvd.,
South San Francisco, CA 94080, U.S.A.
Ryan T. Koehler
Telik, Inc., Discovery Technologies Division, 750 Gateway Blvd.,
South San Francisco, CA 94080, U.S.A.
Abstract
Different representations of molecules, based on distinct sets of properties
can yield different perspectives of the issues involved in library
design. In particular, different chemical representations can give rise to
very different estimates of required library sizes. We provide a
preliminary mathematical framework that examines the size of libraries
required to adequately sample the spaces corresponding to some commonly
used property sets. Introduction of conformational flexibility is also
discussed as a means of increasing coverage of chemical libraries, while
at the same time considering the thermodynamic consequences of flexibility
upon detectable activity. Our theoretical analysis reveals that the
property spaces currently in use are extremely large and unlikely to provide
adequate discrimination among compounds.
Keywords
conformational flexibility, diversityanalysis, diversity measure,
library design, moleculardescriptors, molecular representation,
pharmacophorerepresentation, small molecule libraries
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