Quantum Chemical Exploration of Fentanyl and Its Analogs - Conformational Landscapes and Energetics in Solution

Sep 29, 2026

Opioids are clinical drugs prescribed for moderate-to-severe pain, yet they cause serious adverse effects including bradycardia, constipation, and respiratory depression, and their addictive nature contributes to a U.S. drug epidemic. This work provides a quantum-chemical dataset of 3081 optimized geometries and relative Gibbs free energies at physiological temperature for fentanyl and 33 aqueous analogs. The study identifies a dominant low-energy cis conformation, finds weak correlation between solution conformations/energetics and experimental binding affinity/potency, and suggests receptor interactions govern binding and activity.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Introduction

Opioid agonists and MOR signaling bias

Computational and experimental background for MOR activation

Study context and molecular interactions

This article is licensed under CC-BY 4.0 [http://pubs.acs.org/journal/acsodf](http://pubs.acs.org/journal/acsodf) Article Quantum Chemical Exploration of Fentanyl and Its Analogs: Conformational Landscapes and Energetics in Solution Published as part of ACS Omega special issue “Undergraduate Research as the Stimulusfor Scientific Progress in the USA”. Kimberlyn A. McKnight,§ E. Liyah Reed,§ Caroline S. Glick, * Leah A. Juechter, Cristina A. Guevara, Caitlin E. Scott, and George C. Shields * Cite This: ACS Omega 2025, 10, 58900−58914 Read Online | | | | | | | | --- | --- | --- | --- | --- | --- | | ACCESS | Metrics & More | | Article Recommendations | | *sı Supporting Information | ABSTRACT: Opioids are clinical drugs prescribed to manage moderate and severe pain; however, they have negative side effects such as bradycardia, constipation, and respiratory depression. Their addictive properties have led to a drug epidemic and major health crisis in the U.S. Although experimental and computational studies have explored opioid binding and activation of the μ-opioid receptor (MOR), key questions remain about how these interactions relate to physiological properties. We present a quantum chemical data set of 3081 optimized geometries and relative Gibbs free energies, at physiological temperature, for fentanyl and 33 of its analogs in aqueous solution. We find that these compounds are conformationally flexible, and the cis conformation, where the phenyl rings are approximately parallel, is most prevalent among the low-energy isomers. For the low-energy structures of all 34 analogs, we compare the conformations and energetics in solution with experimental binding affinity and potency data, finding little correlation. This suggests that interactions with the receptor, rather than intrinsic conformational preferences alone, play a dominant role in binding and activity. We expect the data set to be useful for future studies of opioid-MOR interactions. ■ INTRODUCTION Opioids are commonly prescribed to manage moderate to severe pain following injury or medical procedures. These substances, such as methadone, morphine, and fentanyl, function as opioid agonists, meaning they bind to opioid receptors to elicit a physiological response. Common responses induce analgesia, euphoria, sedation, respiratory depression, bradycardia, nausea, and vomiting. 1 However, the highly addictive potential of opioids has contributed to a persistent drug epidemic and major public health crisis in the United States. In 2021, fentanyl alone was responsible for 70,000 United States adults’ overdoses. Fentanyl is also the primary agent in the pediatric opioid crisis and has been implicated in 37.5% of pediatric deaths from 1999 to 2021.2 All opioid agonists act primarily on the central nervous system by binding to the μ-opioid receptor (MOR). MOR is a G-protein coupled receptor (GPCR), which is characterized by seven α-helices that span the lipid bilayer. Opioid agonist binding induces a conformational change involving the α -helices and subsequent activation of intracellular signaling pathways. Of particular interest is the distinction between ligands that preferentially activate the Gi-protein pathway, which is associated with analgesia as well as fewer side effects, and those that also activate the β-arrestin pathway, which is more strongly linked to unwanted side effects like respiratory suppression and constipation.3 Experimental studies have shown that ligands that recruit β-arrestin (like fentanyl) form key interactions to MOR helices 3, 6, and 7, while Gi-biased agonists preferentially interact with helix 3 and make fewer contacts with helices 6 and 7. These interactions influence receptor conformation, promoting different movements of the helices that bias signaling toward either Gi or β-arrestin pathways.4 The association between signaling bias and specific physiological effects has driven efforts to design MOR agon

FAQs

What dataset is provided in the study?

A quantum-chemical dataset of 3081 optimized geometries and relative Gibbs free energies at physiological temperature for fentanyl and 33 aqueous analogs.

Which conformations are most prevalent among low-energy isomers?

The low-energy isomers most often feature the cis conformation, where the phenyl rings are approximately parallel.

How do computed conformations and energetics relate to experimental binding and potency?

The study finds little correlation between solution conformations/energetics and experimental binding affinity and potency, implying receptor interactions play a dominant role.

Sep 29, 2026

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