Figure 1.

Schematic diagram representing steps in systems pharmacology modeling of drug–effect relationships. Drug–receptor binding: Ligand (L) and receptor (R) molecules are transported (k₊) into proximity where intrinsic reactions of association (k_on) and dissociation (k_off) occur. Receptor trafficking and turnover: Ligand–receptor complex (C) is internalized (k_int) by endocytosis. In the endosome, the complex can become dissociated and sorted, and ligand and receptor molecules are recycled (k_rec) or degraded (k_deg). New receptors are synthesized in the cell cytosol (k_syn). Signal transduction: The ligand–receptor complex initiates a signaling cascade by activation of G-proteins or enzymes (E, inactive; E*, active), which can activate other enzymes and secondary messengers (e.g., protein kinases) leading to an up or downregulation of genes, transcribed further to mRNA. Subsequently, mRNA is translated to functional proteins (P) that can affect the cell status. Cellular response: the effector proteins can alter cell turnover (e.g., induce cell death or proliferation) and/or function. These processes change the optical intensity of a marker distributed among all cells and their total count is a measure of the pharmacological effect.