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Molecular Structure of Copper and μ-Oxodiiron Octafluorocorrole Derivatives: Insights into Ligand Noninnocence.

ABSTRACT: Single-crystal X-ray structures were obtained for the copper and μ-oxodiiron complexes of 2,3,7,8,12,13,17,18-octafluoro-5,10,15-triphenylcorrole, hereafter denoted as Cu[F8TPC] and {Fe[F8TPC]}2O. A comparison with the crystal structures of other undecasubstituted Cu corroles, including those with H, Ar, Br, I, and CF3 as β-substituents, showed that the degree of saddling increases in the order: H ≲ F < Ar ≲ Br ≲ I < CF3. In other words, Cu[F8TPC] is marginally more saddled than β-unsubstituted Cu triarylcorroles, but substantially less saddled than Cu undecaarylcorroles, β-octabromo-meso-triarylcorroles, and β-octaiodo-meso-triarylcorroles, and far less saddled than Cu β-octakis(trifluoromethyl)-meso-triarylcorroles. As for {Fe[F8TPC]}2O, the moderate quality of the structure did not allow us to draw firm conclusions in regard to bond length alternations in the corrole skeleton and hence also the question of ligand noninnocence. The Fe-O bond distances, 1.712(8) and 1.724(8), however, are essentially identical to those observed for {Fe[TPFPC]}2O, where TPFPC3- is the trianion of 5,10,15-tris(pentafluorophenyl)corrole, suggesting that a partially noninnocent electronic structural description may be applicable for both compounds.

SUBMITTER: Thomas KE

PROVIDER: S-EPMC7203988 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Molecular Structure of Copper and μ-Oxodiiron Octafluorocorrole Derivatives: Insights into Ligand Noninnocence.

Thomas Kolle E KE Settineri Nicholas S NS Teat Simon J SJ Steene Erik E Ghosh Abhik A

ACS omega 20200423 17

Single-crystal X-ray structures were obtained for the copper and μ-oxodiiron complexes of 2,3,7,8,12,13,17,18-octafluoro-5,10,15-triphenylcorrole, hereafter denoted as Cu[F8TPC] and {Fe[F8TPC]}2O. A comparison with the crystal structures of other undecasubstituted Cu corroles, including those with H, Ar, Br, I, and CF3 as β-substituents, showed that the degree of saddling increases in the order: H ≲ F < Ar ≲ Br ≲ I < CF3. In other words, Cu[ ...[more]

PMID: 32391505

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Project description:Chronic pain is a prevalent problem affecting approximately one out of every five adults in the U.S. The most effective way to treat chronic pain is with opioids, but they cause dangerous side effects such as tolerance, addiction, and respiratory depression, which makes them quite deadly. Opioids, such as fentanyl, target the μ-opioid receptor (MOR), which can then bind to the intracellular Gi protein or the β-arrestin protein. The Gi pathway is primarily responsible for pain relief and potential side effects, but the β-arrestin pathway is chiefly responsible for the unwanted side effects. Ideally, an effective pain medication without side effects would bind to MOR, which would bias signaling solely through the Gi pathway. We used the Bio3D library to conduct principal component analysis to compare the cryo-electron microscopy MOR structure in complex with the Gi versus an X-ray crystallography MOR structure with a nanobody acting as a Gi mimic. Our results agree with a previous study by Munro, which concluded that nanobody-bound MOR is structurally different than Gi-bound MOR. Furthermore, we investigated the structural diversity of opioids that can bind to MOR. Quantum mechanical calculations show that the low energy solution structures of fentanyl differ from the one bound to MOR in the experimental structure, and pKa calculations reveal that fentanyl is protonated in aqueous solution. Glide docking studies show that higher energy structures of fentanyl in solution form favorable docking complexes with MOR. Our calculations show the relative abundance of each fentanyl conformation in solution as well as the energetic barriers that need to be overcome to bind to MOR. Docking studies confirm that multiple fentanyl conformations can bind to the receptor. Perhaps a variety of conformations of fentanyl can stabilize multiple conformations of the MOR, which can explain why fentanyl can induce different intracellular signaling and multiple physiological effects.

Dataset Information

Molecular Structure of Copper and μ-Oxodiiron Octafluorocorrole Derivatives: Insights into Ligand Noninnocence.

Publications

Molecular Structure of Copper and μ-Oxodiiron Octafluorocorrole Derivatives: Insights into Ligand Noninnocence.

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