scholarly journals Location of the hydrophobic pocket in the binding site of fentanyl analogs in the µ-opioid receptor

2007 ◽  
Vol 72 (7) ◽  
pp. 643-654
Author(s):  
Ljiljana Dosen-Micovic ◽  
Milovan Ivanovic ◽  
Vuk Micovic
Keyword(s):  
Opioid Receptor ◽  
Binding Pocket ◽  
Receptor Model ◽  
Hydrophobic Pocket ◽  
Optimal Position ◽  
Alkyl Groups ◽  
Fentanyl Analogs ◽  
Position And Orientation ◽  
Cis And Trans ◽  
Opioid Receptor Agonists

Fentanyl is a highly potent and clinically widely used narcotic analgesic. The synthesis of its analogs remains a challenge in an attempt to develop highly selective ?-opioid receptor agonists with specific pharmacological properties. In this paper, the use of flexible molecular docking of several specific fentanyl analogs to the ?-opioid receptor model, in order to test the hypothesis that the hydrophobic pocket accommodates alkyl groups at position 3 of the fentanyl skeleton, is described. The stereoisomers of the following compounds were studied: cis- and trans-3-methylfentanyl, 3,3-dimethylfentanyl, cis- and trans-3-ethylfentanyl, cis- and trans-3-propylfentanyl, cis-3-isopropylfentanyl and cis-3-benzylfentanyl. The optimal position and orientation of these fentanyl analogs in the binding pocket of the ?-receptor, explaining their enantiospecific potency, were determined. It was found that the 3-alkyl group of cis-3R,4S and trans-3S,4S stereoisomers of all the active compounds occupies the hydrophobic pocket between TM5, TM6 and TM7, made up of the amino acids Trp318 (TM7), Ile322 (TM7), Ile301 (TM6) and Phe237 (TM5). However, the fact that this hydrophobic pocket can also accommodate the bulky 3-alkyl substituents of the two inactive compounds: cis-3-isopropylfentanyl, and cis-3-benzylfentanyl, indicates that this hydrophobic pocket in the employed receptor model is probably too large. .

INTERACTION OF BRIDGED PIPERAZINE DERIVATIVES WITH THE μ-OPIOID RECEPTOR — A THEORETICAL MODEL

2010 ◽  
Vol 09 (supp01) ◽  
pp. 49-63
Author(s):  
VUK MICOVIC ◽  
IVAN JURANIC
Keyword(s):  
Opioid Receptor ◽  
Steric Interaction ◽  
Receptor Complex ◽  
Optimal Position ◽  
Piperazine Derivatives ◽  
B3lyp Method ◽  
Electrostatic Contribution ◽  
Fentanyl Analogs ◽  
Μ Opioid Receptor ◽  
Position And Orientation

The flexible molecular docking was used to study interactions between a series of 3,6-diazabicyclo[3.1.1]heptanes, 9,10-diazatricyclo[4.2.1.1]decanes, and 2,7-diazatricyclo [4.4.0.0]decanes N-substituted by propanoyl and by arylalkenyl groups, and a model of the μ-opioid receptor. It has been found that the optimal position and orientation of the compounds in the ligand–receptor complex resemble that of fentanyl analogs described earlier.1 This model explains stereochemical effects on binding of the two series of 3,6-diazabicyclo[3.1.1]heptanes, suggesting that the steric interaction of the bridge methylenic group plays the major role in modulating μ-receptor affinity of those molecules. Ab initio B3LYP method was used to determine electrostatic potentials of different bridged piperazine derivatives, and to estimate electrostatic contribution to the ligand–receptor complex stability.

scholarly journals A comprehensive evaluation of the potential binding poses of fentanyl and its analogs at the µ-opioid receptor

2021 ◽  
Author(s):  
Bing Xie ◽  
Alexander Goldberg ◽  
Lei Shi
Keyword(s):  
Opioid Receptor ◽  
Comprehensive Evaluation ◽  
Computational Study ◽  
Energy Landscape ◽  
Drug Market ◽  
Binding Pocket ◽  
Structural Basis ◽  
Binding Mechanism ◽  
Fentanyl Analogs ◽  
Dynamics Simulations

Fentanyl and its analogs are selective agonists of the µ-opioid receptor (MOR). Among novel synthetic opioids (NSOs), they dominate the recreational drug market and are the main culprits for the opioid crisis, which has been exacerbated by the COVID-19 pandemic. By taking advantage of the crystal structures of the MOR, several groups have investigated the binding mechanism of fentanyl, but have not reached a consensus, in terms of both the binding orientation and the fentanyl conformation. Thus, the binding mechanism of fentanyl at the MOR remains an unsolved and challenging question. Here, we carried out a systematic computational study to investigate the preferred fentanyl conformations, and how these conformations are being accommodated in the MOR binding pocket. We characterized the free energy landscape of fentanyl conformations with metadynamics simulations, as well as performed long-timescale molecular dynamics simulations to compare and evaluate several possible fentanyl binding conditions. Our results indicate that the most preferred binding pose in the MOR binding pocket corresponds well with the minima on the energy landscape of fentanyl in the absence of the receptor, while the energy landscape can be reconfigured by modifying the fentanyl scaffold. The interactions with the receptor may stabilize a slightly unfavored fentanyl conformation in an alternative binding pose. By extending similar investigations to fentanyl analogs, our findings establish a structure-activity relationship of fentanyl binding at the MOR. In addition to providing a structural basis to understand the potential toxicity of the emerging NSOs, such insights will contribute to developing new, safer analgesics.

scholarly journals Structural requirements for ligands of the δ-opioid receptor

2009 ◽  
Vol 74 (11) ◽  
pp. 1207-1217 ◽  
Author(s):  
Vuk Micovic ◽  
Milovan Ivanovic ◽  
Ljiljana Dosen-Micovic
Keyword(s):  
Opioid Receptor ◽  
Binding Pocket ◽  
Hydroxyl Group ◽  
Opioid Ligands ◽  
Chiral Compounds ◽  
Alkyl Groups ◽  
Selective Ligands ◽  
Ligand Interactions ◽  
Automated Docking ◽  
Δ Opioid Receptor

The ?-opioid receptor is sensitive to ligand geometry. In order to assist the synthesis of new ?-selective opioid ligands, the structure elements of ?-selective opioid ligands necessary for their effective binding were investigated. The automated docking procedure with a flexible ligand was used to simulate the binding of 17 ?-selective ligands to the ?-receptor. It was found that voluminous N-alkyl groups reduce the binding potency of naltrindole derivatives by preventing the ligands from adopting the preferred conformation in the receptor. This was confirmed by enantiospecific binding of chiral compounds where only one enantiomer adopts the naltrindole-like preferred conformation in the binding pocket. Voluminous groups replacing the hydroxyl group in the 3-hydroxybenzyl fragment of naltrindole analogs reduce the binding potency due to unfavorable steric interactions with the receptor. The two diastereoisomers of the potent ?-opioid ligand SNC80 confirmed the preferred binding conformation and the major receptor-ligand interactions.

scholarly journals Cover Feature: Synthesis and Assessment of Fused β‐Carboline Derivatives as Kappa Opioid Receptor Agonists (12/2021)

ChemMedChem ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. 1834-1834
Author(s):  
Veena D. Yadav ◽  
Lalan Kumar ◽  
Poonam Kumari ◽  
Sakesh Kumar ◽  
Maninder Singh ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Receptor Agonists ◽  
Opioid Receptor Agonists

Effects of kappa opioid receptor agonists on attention as assessed by a 5-choice serial reaction time task in rats

2007 ◽  
Vol 53 (8) ◽  
pp. 930-941 ◽  
Author(s):  
Harlan E. Shannon ◽  
Elizabeth L. Eberle ◽  
Charles H. Mitch ◽  
David L. McKinzie ◽  
Michael A. Statnick
Keyword(s):  
Reaction Time ◽  
Opioid Receptor ◽  
Reaction Time Task ◽  
Serial Reaction Time Task ◽  
Kappa Opioid Receptor ◽  
Serial Reaction Time ◽  
Kappa Opioid ◽  
Time Task ◽  
Serial Reaction ◽  
Opioid Receptor Agonists

scholarly journals Characterization of the Acetate Binding Pocket in the Methanosarcina thermophila Acetate Kinase

2005 ◽  
Vol 187 (7) ◽  
pp. 2386-2394 ◽  
Author(s):  
Cheryl Ingram-Smith ◽  
Andrea Gorrell ◽  
Sarah H. Lawrence ◽  
Prabha Iyer ◽  
Kerry Smith ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Binding Site ◽  
Binding Pocket ◽  
Acetate Kinase ◽  
Phosphoryl Group ◽  
Acetyl Phosphate ◽  
Hydrophobic Pocket ◽  
Methanosarcina Thermophila ◽  
Methyl Group ◽  
Substrate Binding Sites

ABSTRACT Acetate kinase catalyzes the reversible magnesium-dependent synthesis of acetyl phosphate by transfer of the ATP γ-phosphoryl group to acetate. Inspection of the crystal structure of the Methanosarcina thermophila enzyme containing only ADP revealed a solvent-accessible hydrophobic pocket formed by residues Val93, Leu122, Phe179, and Pro232 in the active site cleft, which identified a potential acetate binding site. The hypothesis that this was a binding site was further supported by alignment of all acetate kinase sequences available from databases, which showed strict conservation of all four residues, and the recent crystal structure of the M. thermophila enzyme with acetate bound in this pocket. Replacement of each residue in the pocket produced variants with Km values for acetate that were 7- to 26-fold greater than that of the wild type, and perturbations of this binding pocket also altered the specificity for longer-chain carboxylic acids and acetyl phosphate. The kinetic analyses of variants combined with structural modeling indicated that the pocket has roles in binding the methyl group of acetate, influencing substrate specificity, and orienting the carboxyl group. The kinetic analyses also indicated that binding of acetyl phosphate is more dependent on interactions of the phosphate group with an unidentified residue than on interactions between the methyl group and the hydrophobic pocket. The analyses also indicated that Phe179 is essential for catalysis, possibly for domain closure. Alignments of acetate kinase, propionate kinase, and butyrate kinase sequences obtained from databases suggested that these enzymes have similar catalytic mechanisms and carboxylic acid substrate binding sites.

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