Chemical and biological profiling of an annotated compound library directed to the nuclear receptor family.

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.

[1]  Ruben Abagyan,et al.  Nuclear hormone receptor targeted virtual screening. , 2003, Journal of medicinal chemistry.

[2]  John N Weinstein,et al.  Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. , 2004, Cancer cell.

[3]  Dragos Horvath,et al.  Neighborhood Behavior of in Silico Structural Spaces with Respect to in Vitro Activity Spaces-A Novel Understanding of the Molecular Similarity Principle in the Context of Multiple Receptor Binding Profiles , 2003, J. Chem. Inf. Comput. Sci..

[4]  Nikolay P Savchuk,et al.  Exploring the chemogenomic knowledge space with annotated chemical libraries. , 2004, Current opinion in chemical biology.

[5]  G. Müller,et al.  Medicinal chemistry of target family-directed masterkeys. , 2003, Drug discovery today.

[6]  Mark Johnson,et al.  Using Molecular Equivalence Numbers To Visually Explore Structural Features that Distinguish Chemical Libraries , 2002, J. Chem. Inf. Comput. Sci..

[7]  Michael I. Jordan,et al.  Chemogenomic profiling: identifying the functional interactions of small molecules in yeast. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[8]  P P Humphrey,et al.  International Union of Pharmacology. XIX. The IUPHAR receptor code: a proposal for an alphanumeric classification system. , 1998, Pharmacological reviews.

[9]  Alice Lee,et al.  The impact of combinatorial chemistry on drug discovery. , 2003, Current opinion in drug discovery & development.

[10]  E. Berg,et al.  An integrative biology approach for analysis of drug action in models of human vascular inflammation , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[11]  Hans-Joachim Böhm,et al.  A guide to drug discovery: Hit and lead generation: beyond high-throughput screening , 2003, Nature Reviews Drug Discovery.

[12]  G. Bemis,et al.  The properties of known drugs. 1. Molecular frameworks. , 1996, Journal of medicinal chemistry.

[13]  David M. Rocke,et al.  Predicting ligand binding to proteins by affinity fingerprinting. , 1995, Chemistry & biology.

[14]  Phillip Gribbon,et al.  High-throughput drug discovery: what can we expect from HTS? , 2005, Drug discovery today.

[15]  D Horvath,et al.  From hit to lead. Analyzing structure-profile relationships. , 2001, Journal of medicinal chemistry.

[16]  Ruedi Stoop,et al.  An Ontology for Pharmaceutical Ligands and Its Application for in Silico Screening and Library Design , 2002, J. Chem. Inf. Comput. Sci..

[17]  Johan Auwerx,et al.  Nuclear receptors and the control of metabolism. , 2003, Annual review of physiology.

[18]  N. Paul,et al.  Recovering the true targets of specific ligands by virtual screening of the protein data bank , 2004, Proteins.

[19]  S. Frye.  Structure-activity relationship homology (SARAH): a conceptual framework for drug discovery in the genomic era. , 1999, Chemistry & biology.

[20]  E. Sausville,et al.  Mining the National Cancer Institute's tumor-screening database: identification of compounds with similar cellular activities. , 2002, Journal of medicinal chemistry.

[21]  Vincent Laudet,et al.  Principles for modulation of the nuclear receptor superfamily , 2004, Nature Reviews Drug Discovery.

[22]  Christophe Cleva,et al.  Chemical substructures in drug discovery. , 2003, Drug discovery today.

[23]  Philip M Dean,et al.  Probes for chemical genomics by design. , 2002, Drug discovery today.

[24]  E. Jacoby,et al.  Chemogenomics: an emerging strategy for rapid target and drug discovery , 2004, Nature Reviews Genetics.

[25]  Tudor I. Oprea,et al.  WOMBAT: World of Molecular Bioactivity , 2005 .