Decoding the κ Opioid Receptor (KOR): Advancements in Structural Understanding and Implications for Opioid Analgesic Development.

The opioid crisis in the United States is a significant public health issue, with a nearly threefold increase in opioid-related fatalities between 1999 and 2014. In response to this crisis, society has made numerous efforts to mitigate its impact. Recent advancements in understanding the structural intricacies of the κ opioid receptor (KOR) have improved our knowledge of how opioids interact with their receptors, triggering downstream signaling pathways that lead to pain relief. This review concentrates on the KOR, offering crucial structural insights into the binding mechanisms of both agonists and antagonists to the receptor. Through comparative analysis of the atomic details of the binding site, distinct interactions specific to agonists and antagonists have been identified. These insights not only enhance our understanding of ligand binding mechanisms but also shed light on potential pathways for developing new opioid analgesics with an improved risk-benefit profile.

Understanding how water models affect the anomalous pressure dependence of their diffusion coefficients.

The self-diffusion coefficient of water shows an anomalous increase with increasing hydrostatic pressure up to a broad maximum (PmD) near 1 kbar at 298 K, which has been attributed to pressure effects on the tetrahedral hydrogen bond network of water. Moreover, the ability of a water model to reproduce anomalous properties of water is a signature that it is reproducing the network. Here, water was simulated between 1 bar and 5 kbar using three water models, two four-site (with all charges in the molecular plane) and one single-site multipole (which accounts for out-of-molecular plane charge), that have reasonable pressure-temperature properties. For these three models, the diffusion coefficients display a maximum in the pressure dependence and the radial distribution functions show good agreement with the limited experimental structural data at high pressure that are available. In addition, a variety of properties associated with the network are examined, including hydrogen bond lifetimes and occupancies, three-body angle distributions, and tetrahedral order parameters. Results suggest that the initial increasing diffusion with pressure is because hydrogen bonds are distorted and thus weakened by pressure, but above PmD, the hydrogen bonds are weakened to the point it behaves more like a normal liquid. In other words, the PmD may be a measure of the angular strength of hydrogen bonds. In addition, since the four-site models over-predict the values of PmD while the multipole model under-predicts it, out-of-plane charge may improve four-site models.