Nuclear Hormone Receptors (NHRs)

1. Nuclear Hormone Receptors (NHRs) Kristina Hettne Safety Assessment AstraZeneca R&D Mölndal, Sweden

2. Outline • General Concepts • Why NHRs? • Project proposition • Theoretic example • Requirements

3. NH2 COOH AF1 DNA Ligand AF2 General Concepts • One of the largest groups of transcription factors • 49 known • Ligands often small and lipophilic • E.g. hormones, fatty acids, bile acids, oxysterols, endo- and xenobiotics • Structural similarities • Co-regulator recruitment • Depends on conformational changes induced by the ligand, and also by the promoter and cellular context

4. Why NHRs? • They regulate a broad spectrum of processes, including reproduction, development and general metabolism • Tissue distribution of co-factors varies and different ligands induce NHR binding with different co-factors tissue-specific therapeutics • Receptor cross-talk • Need for pathway mapping and annotation tools

5. Why NHRs? • Difficulties in ligand specificity a designed ligand often hits other nuclear receptors • Give rise to adverse events

6. Project proposition • Connect ligands with pathways • Bottom-up approach • Ligand à target à secondary targets à pathways à tissues  effects • Knowledge about secondary target pathways give leads to adverse events

7. High throughput screening, virtual screening Ligand library Match against primary and secondary targets Identify secondary target pathways

8. Secondary target pathways • Reproduction problems • Liver failure • Heart problems Adverse events in humans

9. Requirements • Ligand database • Target database (tissue distribution) • Pathway database (inter-linked) • Tools for connecting these layers