Computational methods for studying G protein-coupled receptors (GPCRs)

Kaczor, Agnieszka A.; Rutkowska, Ewelina; Bartuzi, Damian; Targowska-Duda, Katarzyna M.; Matosiuk, Dariusz; Selent, Jana

doi:10.1016/bs.mcb.2015.11.002

Cited by 31 publications

(28 citation statements)

References 197 publications

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“…We conducted molecular modeling studies by means of docking and MD simulations, with the latter being nowadays an important methodology when studying GPCR versatility associated with functioning and ligand recognition. 12,33 In this study, following MD simulations, the snapshots collected during the last 10% of a 1 ns trajectory were analyzed in order to elucidate which functional groups in the targeted morphinans 1 – 6 form intermolecular hydrogen bonds and to characterize the propensity of these moieties to be involved in polar interactions. The influence on an important molecular switch was also examined, specifically, the 3–7 lock, a link between TM3 and TM7 characterized as a hydrogen-bonding interaction formed between D147 3.32 and Y326 7.43 in the μ-OR.…”

Section: Resultsmentioning

confidence: 99%

Molecular Docking, Molecular Dynamics, and Structure–Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists

Noha

Schmidhammer

Spetea

2017

ACS Chem. Neurosci.

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Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via μ-opioid receptor (μ-OR) activation. Our long-standing efforts in the field of opioid analgesics from the class of morphinans led to N-methylmorphinan-6-ones differently substituted at positions 5 and 14 as μ-OR agonists inducing potent analgesia and fewer undesirable effects. Herein we present the first thorough molecular modeling study and structure–activity relationship (SAR) explorations aided by docking and molecular dynamics (MD) simulations of 14-oxygenated N-methylmorphinan-6-ones to gain insights into their mode of binding to the μ-OR and interaction mechanisms. The structure of activated μ-OR provides an essential model for how ligand/μ-OR binding is encoded within small chemical differences in otherwise structurally similar morphinans. We reveal important molecular interactions that these μ-agonists share and distinguish them. The molecular docking outcomes indicate the crucial role of the relative orientation of the ligand in the μ-OR binding site, influencing the propensity of critical non-covalent interactions that are required to facilitate ligand/μ-OR interactions and receptor activation. The MD simulations point out minor differences in the tendency to form hydrogen bonds by the 4,5α-epoxy group, along with the tendency to affect the 3–7 lock switch. The emerged SARs reveal the subtle interplay between the substituents at positions 5 and 14 in the morphinan scaffold by enabling the identification of key structural elements that determine the distinct pharmacological profiles. This study provides a significant structural basis for understanding ligand binding and μ-OR activation by the 14-oxygenated N-methylmorphinan-6-ones, which should be useful for guiding drug design.

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Section: Resultsmentioning

confidence: 99%

Molecular Docking, Molecular Dynamics, and Structure–Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists

Noha

Schmidhammer

Spetea

2017

ACS Chem. Neurosci.

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“…The progress in computational medicinal chemistry has provided new possibilities in predicting the 3D‐structures of proteins and has allowed MD simulations predicting protein–protein interactions. The resulting dimers or oligomers can further be used for the design of selective allosteric modulators of the macromolecular complexes or as a basis for virtual screening approaches (see Box ) …”

Section: Oligomerization Of P2yrsmentioning

confidence: 99%

P2Y₁‐like nucleotide receptors—Structures, molecular modeling, mutagenesis, and oligomerization

Neumann

Müller

Namasivayam

2020

WIREs Comput Mol Sci

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The P2Y receptors (P2YRs) are G protein‐coupled receptors (GPCRs) consisting of eight members, subdivided into two groups, P2Y1‐ and P2Y12‐like receptor subtypes. They are activated by extracellular nucleotides and represent current (P2Y2, P2Y12) or potential future drug targets. The chemical nature of the highly polar endogenous agonists represents a challenge in the discovery and design of potent and bioavailable compounds. A number of mutants and several homology models of P2YR subtypes have been created and updated on the basis of the recently published X‐ray crystal structures of the human P2Y1 and P2Y12Rs. The models were used for prediction of the binding sites of agonists and antagonists, and mutants were constructed for confirmation. Pharmacological data on mutants published for the P2Y1‐like receptors (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11R) were evaluated to analyze the role of specific amino acids and that of corresponding amino acid residues in related P2Y receptor subtypes. In several P2YR subtypes, an ionic lock between extracellular loop 2 and transmembrane region VII was postulated to be essential for agonist‐induced receptor activation. Mutagenesis and homology modeling data suggest that the nucleotide antagonist (1′R,2′S,4′S,5′S)‐4‐(2‐iodo‐6‐methylaminopurin‐9‐yl)‐1‐[(phosphato)methyl]‐2‐(phosphato)bicyclo[3.1.0]hexane (MRS2500), which was co‐crystallized with the human P2Y1R, binds differently from agonistic nucleotides to a site partly overlapping with that of orthosteric agonists. Hetero‐oligomerization of P2YRs with other P2YR subtypes or other GPCRs may allosterically modulate receptor‐ligand interactions and/or G protein coupling. The collected information will contribute to the understanding of the architecture of P2Y1‐like nucleotide receptors and will consequently be useful for the design of novel agonists and antagonists. This article is categorized under: Molecular and Statistical Mechanics > Free Energy Methods Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Interactions Software > Molecular Modeling

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“…The number of methods helpful in allosteric site prediction were reviewed recently [ 14 , 15 ]. In particular, the AlloSteric Database serves as a source of knowledge on allosteric sites known so far [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Signaling within Allosteric Machines: Signal Transmission Pathways Inside G Protein-Coupled Receptors

2017

Self Cite

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In recent years, our understanding of function of G protein-coupled receptors (GPCRs) has changed from a picture of simple signal relays, transmitting only a particular signal to a particular G protein heterotrimer, to versatile machines, capable of various responses to different stimuli and being modulated by various factors. Some recent reports provide not only the data on ligands/modulators and resultant signals induced by them, but also deeper insights into exact pathways of signal migration and mechanisms of signal transmission through receptor structure. Combination of these computational and experimental data sheds more light on underlying mechanisms of signal transmission and signaling bias in GPCRs. In this review we focus on available clues on allosteric pathways responsible for complex signal processing within GPCRs structures, with particular emphasis on linking compatible in silico- and in vitro-derived data on the most probable allosteric connections.

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Computational methods for studying G protein-coupled receptors (GPCRs)

Cited by 31 publications

References 197 publications

Molecular Docking, Molecular Dynamics, and Structure–Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists

Molecular Docking, Molecular Dynamics, and Structure–Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists

P2Y₁‐like nucleotide receptors—Structures, molecular modeling, mutagenesis, and oligomerization

Signaling within Allosteric Machines: Signal Transmission Pathways Inside G Protein-Coupled Receptors

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Computational methods for studying G protein-coupled receptors (GPCRs)

Cited by 31 publications

References 197 publications

Molecular Docking, Molecular Dynamics, and Structure–Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists

Molecular Docking, Molecular Dynamics, and Structure–Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists

P2Y1‐like nucleotide receptors—Structures, molecular modeling, mutagenesis, and oligomerization

Signaling within Allosteric Machines: Signal Transmission Pathways Inside G Protein-Coupled Receptors

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Product

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P2Y₁‐like nucleotide receptors—Structures, molecular modeling, mutagenesis, and oligomerization