Insights From Molecular Dynamics Simulations of a Number of G-Protein Coupled Receptor Targets for the Treatment of Pain and Opioid Use Disorders

Ribeiro, João Marcelo Lamim; Filizola, Marta

doi:10.3389/fnmol.2019.00207

Cited by 21 publications

(23 citation statements)

References 76 publications

(129 reference statements)

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“…A shift in TM3, TM6 and TM7 in the simulation runs with the agonists created a void resulting in receptor activation through a bulk water influx into the binding pocket [69]. Similar observations were reported for several class A family members of GPCRs including µ-opioid receptors and adenosine receptors [70][71][72][73].…”

Section: Simulation Study Of Antagonistssupporting

confidence: 73%

Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

et al. 2020

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GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist ∆9-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still require unambiguous confirmation. In the present study, we constructed a homology model of the human GPR18 based on an ensemble of three GPCR crystal structures to investigate the binding modes of the agonist THC and the recently reported antagonists which feature an imidazothiazinone core to which a (substituted) phenyl ring is connected via a lipophilic linker. Docking and molecular dynamics simulation studies were performed. As a result, a hydrophobic binding pocket is predicted to accommodate the imidazothiazinone core, while the terminal phenyl ring projects towards an aromatic pocket. Hydrophobic interaction of Cys251 with substituents on the phenyl ring could explain the high potency of the most potent derivatives. Molecular dynamics simulation studies suggest that the binding of imidazothiazinone antagonists stabilizes transmembrane regions TM1, TM6 and TM7 of the receptor through a salt bridge between Asp118 and Lys133. The agonist THC is presumed to bind differently to GPR18 than to the distantly related CB receptors. This study provides insights into the binding mode of GPR18 agonists and antagonists which will facilitate future drug design for this promising potential drug target.

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Section: Simulation Study Of Antagonistssupporting

confidence: 73%

Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

et al. 2020

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“…The observed differences in the in vitro activity profiles of DALDA, [Dmt 1 ]DALDA, and KGOP01 ( Table 1 ) encouraged in silico investigations of their binding modes at the MOR. The recently published crystal structure of the active conformation of the MOR (PDB ID: 5C1M; resolution: 2.1 Å) [ 24 ] provides the structural basis for understanding important aspects of MOR pharmacology and its function [ 22 , 24 , 45 ]. In order to examine possible binding conformations of the targeted peptide analogues to the MOR, docking experiments were performed using GOLD [ 46 ], and LigandScout [ 47 ] was used to analyze differences in receptor–ligand interactions.…”

Section: Resultsmentioning

confidence: 99%

“…Since the breakthrough of GPCR crystallization one decade ago, the understanding of the complex biology of GPCR activation and signaling has dramatically increased [ 16 , 17 , 18 , 19 ]. Substantial advances in structural biology of GPCRs were possible by means of innovative methodological and powerful computational systems [ 20 , 21 , 22 ]. Due to its therapeutic relevance, the MOR is among the few GPCRs determined in different activation states, with the first X-ray crystal structure of the murine MOR published in 2012 in complex with the irreversible morphinan antagonist β-funaltrexamine (PDB ID: 4DKL) [ 23 ], and the 3D-structure in the active conformation reported in 2015, where the receptor was co-crystallized with the morphinan agonist BU72 (PDB ID: 5C1M) [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, the high resolution cryo-electron microscopy (cryo-EM) structure of the MOR (PDB ID: 6DDF) bound to the agonist peptide DAMGO ( Figure 1 ) was reported [ 25 ], offering an important view on the structural features that contribute to the G i protein-coupling specificity of the MOR. The available crystal structures of the MOR together with efficient computational methods (i.e., molecular docking and molecular dynamics simulations) provide essential insights into binding modes of ligands to the receptor, with the gained knowledge being successfully translated into the discovery of novel bioactive molecules [ 22 , 26 , 27 ]. Most of molecular modeling reports on the active and inactive structures of the MOR targeted small molecules as ligands, with only few studies employing peptides, mostly DAMGO, as the prototypical MOR selective synthetic analogue of the natural peptides enkephalin [ 25 , 28 , 29 ], endomorphin-2, and dermorphin, as endogenous opioid ligands for the MOR [ 30 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

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Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the Mu Opioid Receptor

et al. 2020

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The mu opioid receptor (MOR) is the primary target for analgesia of endogenous opioid peptides, alkaloids, synthetic small molecules with diverse scaffolds, and peptidomimetics. Peptide-based opioids are viewed as potential analgesics with reduced side effects and have received constant scientific interest over the years. This study focuses on three potent peptide and peptidomimetic MOR agonists, DALDA, [Dmt1]DALDA, and KGOP01, and the prototypical peptide MOR agonist DAMGO. We present the first molecular modeling study and structure–activity relationships aided by in vitro assays and molecular docking of the opioid peptide analogues, in order to gain insight into their mode of binding to the MOR. In vitro binding and functional assays revealed the same rank order with KGOP01 > [Dmt1]DALDA > DAMGO > DALDA for both binding and MOR activation. Using molecular docking at the MOR and three-dimensional interaction pattern analysis, we have rationalized the experimental outcomes and highlighted key amino acid residues responsible for agonist binding to the MOR. The Dmt (2′,6′-dimethyl-L-Tyr) moiety of [Dmt1]DALDA and KGOP01 was found to represent the driving force for their high potency and agonist activity at the MOR. These findings contribute to a deeper understanding of MOR function and flexible peptide ligand–MOR interactions, that are of significant relevance for the future design of opioid peptide-based analgesics.

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“…Moreover, K. M. Honorio et al utilized dynamic protein methods to design human DPP4 inhibitors that might fit into the catalytic region. The study shows that human DPP4 functional motion significantly affects the design of such inhibitors (Pantaleão, 2018;Ribeiro & Filizola, 2019). Further, structural and modeling studies of human ACE2 suggest spatial interactions with SARS-CoV-2 might be varied among COVID-19 patients due to genetic variants in ACE2, which leads to susceptibility variations against the virus (Hussain, 2020).…”

Section: Introductionmentioning

confidence: 89%

Exploring structural dynamics of the MERS-CoV receptor DPP4 and mutant DPP4 receptors

Alaofi

2020

Journal of Biomolecular Structure and Dynamics

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Mouse DPP4 (mDPP4) receptor is not a functional receptor for MERS-CoV while human DPP4 (hDPP4) is, despite the high similarities between hDPP4 and mDPP4 receptors. The variability of DPP4 receptors against MERS-CoV is not fully investigated, especially conformational and structural differences. Therefore, investigating the conformational differences of the DPP4 receptors can aid in developing new small animal models for MERS-CoV vaccines and antiviral agents evaluation. Here we used MD simulations and docking techniques to investigate these structural differences in DPP4 receptors. The results showed chimeric mouse mDPP4 (cmDPP4) has a similar compact conformation as wild-type hDPP4 based on the structural analysis. Interestingly, a single Thr288Ala mutation induced a relaxed conformation in chimeric 2 hDPP4 (c2hDPP4) and chimeric 2 mDPP4 (c2mDPP4); in addition to its significant effect on the DPP4 flexibility. The Thr288 residue is known for its critical function in MERS-CoV RBD interaction. Moreover, MERS-CoV RBD adopts a "standing" conformation when docked to hDPP4 and cmDPP4 in blade IV and V regions. In conclusion, the results could explain the functionality differences between mouse and human DPP4 receptors against MERS-CoV. However, further structural studies are needed to evaluate how DPP4 conformations affects MERS-CoV RBD binding and affinity.

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Insights From Molecular Dynamics Simulations of a Number of G-Protein Coupled Receptor Targets for the Treatment of Pain and Opioid Use Disorders

Cited by 21 publications

References 76 publications

Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the Mu Opioid Receptor

Exploring structural dynamics of the MERS-CoV receptor DPP4 and mutant DPP4 receptors

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