Ligand Pathways in Nuclear Receptors

Nuclear receptors (NRs) are ligand-inducible transcription factors that play an essential role in a multitude of physiological processes as well as diseases, rendering them attractive drug targets. Crystal structures revealed the binding site of NRs to be buried in the core of the protein, with no obvious route for ligands to access this cavity. The process of ligand binding is known to be an often-neglected contributor to the efficacy of drug candidates and is thought to influence the selectivity and specificity of NRs. While experimental methods generally fail to highlight the dynamic processes of ligand access or egress on the atomistic scale, computational methods have provided fundamental insight into the pathways connecting the buried binding pocket to the surrounding environment. Methods based on molecular dynamics (MD) and Monte Carlo simulations have been applied to identify pathways and quantify their capability to transport ligands. Here, we systematically review findings of more than 20 years of research in the field, including the applied methodology and controversies. Further, we establish a unified nomenclature to describe the pathways with respect to their location relative to protein secondary structure elements and summarize findings relevant to drug design. Lastly, we discuss the effect of NR interaction partners such as coactivators and corepressors, as well as mutations on the pathways.