Molecular dynamics of fentanyl bound to μ-opioid receptor

Lipiński, Piotr F. J.; Jarończyk, Małgorzata; Dobrowolski, Jan Cz.; Sadlej, Joanna

doi:10.1007/s00894-019-3999-2

Cited by 63 publications

(110 citation statements)

References 53 publications

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“…Morphine was also shown to form stable hydrophobic interactions with His297 (protonation state unclear) in a recent MD study. 17 The de novo binding simulations of the Filizola group showed that oliceridine (TRV-130) which has an atypical chemical scaffold binds mOR via water-mediated interactions between the charged amine group and Asp147, while frequently contacting His297 (protonation state unclear). 32 While consistent with these studies, our data uncovered an unexpected role of the tautomer state in modulating the fentanyl-binding mechanism.…”

Section: Concluding Discussionmentioning

confidence: 99%

“…Considering the lack of sodium presence in the active mOR, two previous MD studies used a protonated Asp114, 8,10 while published work did not specify the protonation state. 17,31,32 Recently, the pK a of D 2.50 in M2 muscarinic acetylcholine receptor (m2R) was calculated using the Poisson-Boltzmann method with a protein electric constant of 4. 35 The calculation gave a pK a of 8-12 when sodium is 5 Å away from D 2.50 .…”

Section: Concluding Discussionmentioning

confidence: 99%

“…The aforementioned mutagenesis experiments performed to probe the role of Asp147 and His297 were inconclusive due to excessive non-specific binding of fentanyl. 14 Docking 15,16 and long-time molecular dynamics (MD) simulations 17 based on the docked structure of fentanyl in mOR confirmed the stability of the orthosteric binding mode involving the salt bridge with Asp147; however, the role of His297 has not been explored.…”

Section: Introductionmentioning

confidence: 99%

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How mu-Opioid Receptor Recognizes Fentanyl

Mahinthichaichan

Shen

et al. 2020

Preprint

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The opioid crisis has escalated during the COVID-19 pandemic. More than half of the overdose-related deaths are related to synthetic opioids represented by fentanyl which is a potent agonist of mu-opioid receptor (mOR). In recent years, crystal structures of mOR complexed with morphine derivatives have been determined; however, structural basis of mOR activation by fentanyl-like synthetic opioids remains lacking. Exploiting the X-ray structure of mOR bound to a morphinan ligand and several state-of-the-art simulation techniques, including weighted ensemble and continuous constant pH molecular dynamics, we elucidated the detailed binding mechanism of fentanyl with mOR. Surprisingly, in addition to the orthosteric site common to morphinan opiates, fentanyl can move deeper and bind mOR through hydrogen bonding with a conserved histidine H297, which has been shown to modulate mOR's ligand affinity and pH dependence in mutagenesis experiments, but its precise role remains unclear. Intriguingly, the secondary binding mode is only accessible when H297 adopts a neutral HID tautomer. Alternative binding modes and involvement of tautomer states may represent general mechanisms in G protein-coupled receptor (GPCR)-ligand recognition. Our work provides a starting point for understanding mOR activation by fentanyl analogs that are emerging at a rapid pace and assisting the design of safer analgesics to combat the opioid crisis. Current protein simulation studies employ standard protonation and tautomer states; our work demonstrates the need to move beyond the practice to advance our understanding of protein-ligand recognition.

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Section: Concluding Discussionmentioning

confidence: 99%

Section: Concluding Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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How mu-Opioid Receptor Recognizes Fentanyl

Mahinthichaichan

Shen

et al. 2020

Preprint

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“…Further, Phe3 in 1 and Phe4 in DAMGO are situated in the same S2 site. S2 is also occupied by phenyl rings of small molecular agonist BU72 in 5 C1 M [12] crystal structure ( Figure S18) or of fentanyl [32,33] according to molecular modeling ( Figure S19). The analogues of 1 were predicted to bind in orientations largely similar to that of the parent compound.…”

Section: Molecular Modelingmentioning

confidence: 99%

Pharmacological Profile and Molecular Modeling of Cyclic Opioid Analogues Incorporating Various Phenylalanine Derivatives

Adamska‐Bartłomiejczyk

Lipiński

Piekielna-Ciesielska

et al. 2020

ChemMedChem

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Peptide‐based agonists of the μ opioid receptor (μOR) are promising therapeutic candidates for pain relief with reduced side effects compared to morphine. A deep understanding of μOR–ligand interactions is necessary for future design of peptide‐based opioid analgesics. To explore the requirements of the μOR binding pocket, eight new analogues of our cyclic peptide Tyr‐c[d‐Lys−Phe−Phe−Asp]NH2 displaying high μOR affinity were synthesized, in which Phe in either the third or fourth position was replaced by various derivatives of this amino acid (β3‐Phe, homoPhe, β3‐homoPhe and PhGly). The aim of this research was to examine the structural effects of such modifications on the bioactivity, and both experimental and theoretical methods were used. The binding of the cyclic analogues to all three OR types (μ, δ, κ) was assessed by radioligand competitive binding assay, and their functional activity was determined in a calcium mobilization assay. In order to provide structural hypotheses explaining the obtained experimental affinities, the complexes of the cyclic peptides with μOR were subjected to molecular modeling.

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“…The receptor was placed in a phosphatidylcholine (POPC) membrane and solvated with the TIP3P water model; the CHARMM36 force-field was used. The simulation runtime was 1.2 s [71].…”

Section: Using Molecular Dynamics Simulations To Study Gpcr-ligand Bimentioning

confidence: 99%

Insights from Molecular Dynamics Simulations for GPCR Drug Discovery

Zou¹,

Ewalt²,

Ng³

2019

Preprint

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G protein-coupled receptors (GPCRs) are critical drug targets. GPCRs convey signals from the extracellular to the intracellular environment through G proteins. There is evidence that some ligands that bind to the GPCRs activate different downstream signaling pathways. G protein activation or -arrestin biased signaling involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. Molecular dynamics (MD) simulations are especially valuable for obtaining detailed mechanistic information, including identification of allosteric sites and understanding modulators' interactions between receptors and ligands. Here, we highlight recent simulation studies and methods used to study biased G protein-coupled receptor signaling and their conformational dynamics. We also highlight applications of MD simulations to drug discovery.

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Molecular dynamics of fentanyl bound to μ-opioid receptor

Cited by 63 publications

References 53 publications

How mu-Opioid Receptor Recognizes Fentanyl

How mu-Opioid Receptor Recognizes Fentanyl

Pharmacological Profile and Molecular Modeling of Cyclic Opioid Analogues Incorporating Various Phenylalanine Derivatives

Insights from Molecular Dynamics Simulations for GPCR Drug Discovery

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