Quantum Chemical and Molecular Docking Studies of [(η⁶‑Cp*Rh-Tyr¹)‑Leu-enkephalin]²⁺ to G‑Protein-Coupled μ‑, ∂‑, and κ‑Opioid Receptors and Comparisons to the Neuropeptide [Tyr¹]‑Leu-enkephalin: Conformations, Noncovalent Amino Acid Binding Sites, Binding Energies, Electronic Factors, and Receptor Distortion Forces

Recently reported studies by Kobilka et al. (Nature 2012, 485, 321, 400) and Stevens et al. (Nature 2012, 485, 327) have characterized the structures of the G-protein-coupled μ-, ∂-, and κ-opioid receptors (GPCORs) via X-ray crystallography, including the use of guest, morphinan antagonist, drug analogues. These GPCORs have been shown to control the physiological functions of pain and, therefore, have been designated as a prime target for new, nonaddictive, pain drug discoveries. Moreover, Fish et al. (J. Am. Chem. Soc. 2012, 134, 10321) have recently reported on a chemoselective reaction of GPCR tyrosine-containing peptides with [Cp*Rh­(H2O3)]­(OTf)2 to provide [(η6-Cp*Rh-Tyr#)-GPCR-peptide]­(OTf)2 complexes. For example, the agonist, endogenous neuropeptide [Tyr1]-Leu-enkephalin, 1 (Tyr1-Gly-Gly-Phe-Leu), upon reaction with the Cp*Rh tris aqua complex, at pH 5–6, gave the [(η6-Cp*Rh-Tyr1)-Leu-enkephalin]­(OTf)2 complex 2, also an agonist, which was found to bind to individual and coexpressed μ- and ∂-opioid receptor cells. Therefore, we present, in this contribution, the first comprehensive quantum chemical and molecular docking studies of an organometallic–neuropeptide complex, 2, to structurally characterized μ-, ∂-, and κ-GPCORs. We found that the docked conformations of dication 2 at the three opioid receptors were in similar receptor locations to the natural neuropeptide 1, as well as the morphinan drug derivatives, all antagonists, used in the X-ray structures of the μ-, ∂-, and κ-opioid receptors, but, importantly, had distinctly different noncovalent H-bonding, π–π, and CH−π interactions with the nearby transmembrane receptor amino acids compared to 1, with only H-bonding interactions. Therefore, quantum chemical calculations showed this was due to four critical factors: (a) Dication 2 was found to be a non-zwitterion versus 1 being a zwitterion; (b) significant differences in the electron density and hydrophobic effects of the (η6-Cp*Rh-Tyr1)2+ versus the (Tyr1) moieties on the message paradigm for receptor molecular recognition; (c) binding energies of 2 in comparison to 1, for the opioid receptors; and (d) receptor distortion forces that could possibly hinder binding regimes of 1 and 2, especially to the κ-opioid receptor. Furthermore, we have attempted to understand how these factors might possibly be related to the previously reported EC50 receptor binding values (nM) of agonists 1 and 2 at the μ-, ∂-, and κ-opioid receptors.