Nuclear Receptor Drug Discovery In Vitro Assays

Nuclear receptors (NRs) are a type of protein found in cells that detects steroid and thyroid hormones, as well as a variety of other compounds. These receptors collaborate with other proteins to control the production of specific genes, hence regulating the organism's development, homeostasis, and metabolism. Nuclear receptors are transcription factors because they have the ability to directly bind to DNA and influence the expression of nearby genes. Nuclear receptors regulate gene expression only when a ligand is present. The binding of a ligand to a nuclear receptor causes a conformational change in the receptor, which activates the receptor and causes up- or down-regulation of gene expression.

Pharmacology

Lipophilic molecules such endogenous hormones, vitamins A and D, and xenobiotic hormones attach to nuclear receptors and activate them. Nuclear receptors govern the production of a vast number of genes, therefore ligands that activate these receptors can have a significant impact on the organism. Many of the controlled genes have been linked to a variety of disorders.

• Agonists
  It is typical for endogenous ligands to upregulate gene expression when they bind to their associated nuclear receptors, such as the hormones estradiol and testosterone. The agonist response is the term used to describe the ligand's stimulation of gene expression.
• Antagonists
  In the absence of endogenous ligand, other synthetic nuclear receptor ligands do not appear to affect gene transcription. Through competing binding to the same binding site in the nuclear receptor, they do, however, counteract the effects of the agonist. These ligands are antagonists.
• Inverse agonists
  Finally, in the absence of agonists, some nuclear receptors stimulate a low degree of gene transcription. Inverse agonists are artificial ligands that lower the nuclear receptors' basal level of activation.
• Selective receptor modulators
  Many medications that function by binding to nuclear receptors provide an agonist response in some tissues and an antagonistic reaction in others. Selective receptor modulators (SRMs) are drugs having this dual agonist/antagonist mode of action.

Feature and Classification

Multifunctional proteins called nuclear receptors translate signals from their specific ligands. According to their mode of operation and subcellular distribution in the absence of ligand, NRs can be divided into two major types. Natural hormones and other small lipophilic compounds bind to nuclear receptors in the cytoplasm (type I NR) or nucleus (type II NR) of the cell after diffusing past the cell membrane. Depending on the class of receptor, binding results in a conformational change in the receptor that directs the NRs to DNA transcription regulatory sites, where they either up-regulate or down-regulate gene expression.