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

## TL;DR

This study uses quantum chemistry to explore the shapes and energies of fentanyl and its analogs in water, finding that their flexibility and preferred shapes don't strongly predict how well they bind to opioid receptors.

## Contribution

A quantum chemical dataset of fentanyl and 33 analogs in solution, revealing conformational preferences and their limited correlation with binding potency.

## Key findings

- Fentanyl and its analogs show high conformational flexibility in aqueous solution.
- The cis conformation with parallel phenyl rings is most common among low-energy isomers.
- Conformational preferences in solution show little correlation with experimental binding affinity or potency.

## 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.