Computational Design of β-Fluorinated Morphine Derivatives for pH-specific Binding

Authors

Nayiri Alexander, Chapman UniversityFollow
Makena Augenstein, Chapman UniversityFollow
Matthew Gartner, Chapman UniversityFollow

Document Type

Poster

Publication Date

Spring 5-2022

Faculty Advisor(s)

Dr. Matthew Gartner

Abstract

The opioid epidemic impacted over 12 million Americans in 2019. Although they are effective pain-relieving medications, they carry addictive and dangerous side effects. Opioids, like morphine, bind non-selectively in both central and peripheral tissues; however, dangerous side effects result from central activation. Inflamed conditions of injured tissues have a lower pH (pH=6-6.5) environment than healthy central tissue (pH=7.4). We aim to design a morphine derivative that binds selectively within inflamed tissue using computationally-based molecular extension and dissection techniques. Binding to the mu-opioid receptor (MOR) is dependent on protonation of the biochemically active amine group of morphine. Fluorination of a carbon beta to the tertiary amine group was used in order to reduce the pKa of the ligand through induction. By decreasing the pKa of morphine, protonation remains possible in lower pH environments of inflamed tissue, while remaining primarily deprotonated in healthy tissue. A cyclohexane and pyridine ring were removed to increase conformational flexibility when binding to the MOR and maintaining biological function. Electronic structure calculations were performed with Gaussian16 using the Keck Computational Research Cluster at Chapman University. The theoretical pKa values were determined at the M06-2X/aug-cc-pVDZ//SMD level of theory to calculate the ΔG°aq values for the amine deprotonation reactions. Multiple beta-fluorinated morphine derivatives were made computationally and modeled within the MOR using Maestro: Schrödinger. Derivatives show reductions in pKa and enhanced ligand protein interactions within the MOR. Beta-fluorination decreased the overall pKa values of the morphine derivatives (pKa: 6.1-7.8) relative to morphine. The reductions in pKa reduce the possibility of binding within healthy, central tissue.

Comments

Presented at the Spring 2022 Student Scholar Symposium at Chapman University.

Recommended Citation

Alexander, Nayiri; Augenstein, Makena; and Gartner, Matthew, "Computational Design of β-Fluorinated Morphine Derivatives for pH-specific Binding" (2022). Student Scholar Symposium Abstracts and Posters. 527.
https://digitalcommons.chapman.edu/cusrd_abstracts/527