Quantum Chemical and Molecular Docking Studies of [(畏6-Cp*Rh-Tyr1)-Leu-enkephalin]2+ to G-Protein-Coupled 渭-, 鈭?, and 魏-Opioid Receptors and Comparisons to the Neurope
详细信息 查看全文
- 作者：Irena Efremenko ; Richard H. Fish
- 刊名：Organometallics
- 出版年：2015
- 出版时间：August 24, 2015
- 年：2015
- 卷：34
- 期：16
- 页码：4117-4126
- 全文大小：661K
- ISSN：1520-6041
文摘
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 渭-, 鈭?, and 魏-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 [(畏6-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鈥?, gave the [(畏6-Cp*Rh-Tyr1)-Leu-enkephalin](OTf)2 complex 2, also an agonist, which was found to bind to individual and coexpressed 渭- and 鈭?opioid receptor cells. Therefore, we present, in this contribution, the first comprehensive quantum chemical and molecular docking studies of an organometallic鈥搉europeptide complex, 2, to structurally characterized 渭-, 鈭?, and 魏-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 渭-, 鈭?, and 魏-opioid receptors, but, importantly, had distinctly different noncovalent H-bonding, 蟺鈥撓€, and CH鈭捪€ 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 (畏6-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 魏-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 渭-, 鈭?, and 魏-opioid receptors.