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

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.