Chemical and Biological Profiling of an Annotated Compound Library Directed to the Nuclear Receptor Family

Montserrat      Cases; Ricard      Garcia-Serna; Kristina      Hettne; Marc      Weeber; Johan   V.   Lei; Scott      Boyer; Jordi      Mestres

Abstract

Nuclear receptors form a family of ligand-activated transcription factors that regulate a wide variety of biological processes and are thus generally considered relevant targets in drug discovery. We have constructed an annotated compound library directed to nuclear receptors (NRacl) as a means for integrating the chemical and biological data being generated within this family. Special care has been put in the appropriate storage of annotations by using hierarchical classification schemes for both molecules and nuclear receptors, which takes the ability to extract knowledge from annotated compound libraries to another level. Analysis of NRacl has ultimately led to the identification of scaffolds with highly promiscuous nuclear receptor profiles and to the classification of nuclear receptor groups with similar scaffold promiscuity patterns. This information can be exploited in the design of probing libraries for deorphanization activities as well as for devising screening batteries to address selectivity issues.

Keywords: combinatorial chemistry, high-throughput screening, mdl drug data report (mddr), wombat database

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