According to the Institute of Medicine, 116 million Americans suffer from chronic pain, costing over $500 billion annually. As such, the use of pain‐killing drugs like morphine and oxycodone has increased dramatically over the past decade. Analgesic effects are produced through agonism, or activation, of the body's mu (MOR) and delta (DOR) opioid receptors, which are G‐coupled protein receptors. Tolerance, the decreased analgesic effect of MOR agonists after prolonged use, is a major problem facing opioid pain management. A drug that antagonizes, or inhibits, DOR can greatly reduce the development of tolerance to MOR agonists, offering new pain therapy potentials. One example of a selective DOR antagonist is naltrindole (NTI), which has a similar structure as morphine, except for a cyclopropylmethyl group on its nitrogen substituent and a bulky indole group. The large indole ring negatively interacts with the W318 residue on MOR but is able to bond with W284 residue on the DOR, producing DOR‐selective antagonism. Co‐administration of NTI with morphine represents a potential new approach to producing analgesics with less tolerance. Understanding the structure of this ligand and enzyme may further structure‐based drug designs. The Marquette University High School SMART Team (Students Modeling A Research Topic) modeled naltrindole bound to DOR using 3‐D printing technology. Supported by a grant from the NIH‐CTSA.
Why can't Grandpa drink grapefruit juice with his Lipitor? Why is John hypersensitive to aspirin? The answers lie in a study of cytochrome P450s (CYP101), a family of enzymes that are responsible for the transformation of vitamins, pharmaceuticals and other foreign chemicals into soluble and readily excreted molecules. This goal is achieved primarily by hydroxylation reactions, which occur in these molecules through a series of extremely fast sequential reactions, called an enzymatic cycle. In order to better understand certain intermediates in the cycle, the reaction must be stopped at given points. In a particular variant of cytochrome P450s, the presence of an aspartic acid near the active site causes immediate protonation of the peroxo group, making it impossible to stop the hydroxylation reaction. However, in the mutant form, CYP101 D251N, the aspartic acid is replaced with an asparagine, which blocks protonation on an atomic level. Scientists need to study these molecules and characterize the molecular structures of the reaction intermediates in order to understand what factors affect the process, such as mutation of particular protein sites and blockage by interfering chemicals. The Marquette University High School SMART Team (Students Modeling A Research Topic) modeled both the wild‐type and the D251N mutant of P450cam using MSOE's 3D printing technology. Supported by grants from NIH‐SEPA and NIH‐CTSA.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.