Location of the hydrophobic pocket in the binding site of fentanyl analogs in the mu-opioid receptor
Apstrakt
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 mu-opioid receptor agonists with specific pharmacological properties. In this paper, the use of flexible molecular docking of several specific fentanyl analogs to the mu-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 mu-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 o...ccupies the hydrophobic pocket between TM5, TM6 and TM7, made LIP of the amino acids Trp318 (TM7), Ile322 (TM7), 1001 (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.
Ključne reči:
molecular modeling / fentanyl analogs / ligand-receptor interactions / docking simulationIzvor:
Journal of the Serbian Chemical Society, 2007, 72, 7, 643-654Izdavač:
- Serbian Chemical Soc, Belgrade
DOI: 10.2298/JSC0707643D
ISSN: 0352-5139
WoS: 000248193600002
Scopus: 2-s2.0-34447512873
Kolekcije
Institucija/grupa
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Dosen-Miovic, Ljiljana AU - Ivanović, Milovan AU - Micovic, Vuk PY - 2007 UR - https://cherry.chem.bg.ac.rs/handle/123456789/852 AB - 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 mu-opioid receptor agonists with specific pharmacological properties. In this paper, the use of flexible molecular docking of several specific fentanyl analogs to the mu-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 mu-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 LIP of the amino acids Trp318 (TM7), Ile322 (TM7), 1001 (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. PB - Serbian Chemical Soc, Belgrade T2 - Journal of the Serbian Chemical Society T1 - Location of the hydrophobic pocket in the binding site of fentanyl analogs in the mu-opioid receptor VL - 72 IS - 7 SP - 643 EP - 654 DO - 10.2298/JSC0707643D ER -
@article{ author = "Dosen-Miovic, Ljiljana and Ivanović, Milovan and Micovic, Vuk", year = "2007", abstract = "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 mu-opioid receptor agonists with specific pharmacological properties. In this paper, the use of flexible molecular docking of several specific fentanyl analogs to the mu-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 mu-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 LIP of the amino acids Trp318 (TM7), Ile322 (TM7), 1001 (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.", publisher = "Serbian Chemical Soc, Belgrade", journal = "Journal of the Serbian Chemical Society", title = "Location of the hydrophobic pocket in the binding site of fentanyl analogs in the mu-opioid receptor", volume = "72", number = "7", pages = "643-654", doi = "10.2298/JSC0707643D" }
Dosen-Miovic, L., Ivanović, M.,& Micovic, V.. (2007). Location of the hydrophobic pocket in the binding site of fentanyl analogs in the mu-opioid receptor. in Journal of the Serbian Chemical Society Serbian Chemical Soc, Belgrade., 72(7), 643-654. https://doi.org/10.2298/JSC0707643D
Dosen-Miovic L, Ivanović M, Micovic V. Location of the hydrophobic pocket in the binding site of fentanyl analogs in the mu-opioid receptor. in Journal of the Serbian Chemical Society. 2007;72(7):643-654. doi:10.2298/JSC0707643D .
Dosen-Miovic, Ljiljana, Ivanović, Milovan, Micovic, Vuk, "Location of the hydrophobic pocket in the binding site of fentanyl analogs in the mu-opioid receptor" in Journal of the Serbian Chemical Society, 72, no. 7 (2007):643-654, https://doi.org/10.2298/JSC0707643D . .