Computational insights into the molecular mechanisms of differentiated allosteric modulation at the mu opioid receptor by structurally similar bitopic modulators

Wang, Huiqun; Reinecke, Bethany A.; Zhang, Yan

doi:10.1007/s10822-020-00309-x

Cited by 11 publications

(15 citation statements)

References 84 publications

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“…The use of the allosteric site in addition to the orthosteric pocket in drug design has been referred to as the "exosite model" and "the design of bitopic ligands/drugs" by two separate research communities [938,939]. Modeling methods, including MD simulations, are one of the tools used in the design of bitopic drugs [900,940,941]; however, in these studies lipids are only considered as a passive component and their complete role in substrate selection is not fully elucidated.…”

Section: Other Effects On Lipid Layers-pulmonary Surfactants and Indirect Effect On Membrane Proteinsmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

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Section: Other Effects On Lipid Layers-pulmonary Surfactants and Indirect Effect On Membrane Proteinsmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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“…In the inactive and active MOR the SP of NCQ showed positive allosteric modulation through binding to ABD2. Molecular modelling combined with interaction energy and distance analyses unravelled the molecular mechanisms of allosteric modulation of NAQ and NCQ and emphasized the importance of the chlorine and methoxy substituents of the isoquinoline ring for the allosteric modulatory function of NCQ ( Wang et al, 2020 ).…”

Section: Bitopic Ligands To Study Selectivity and Functional Selectiv...mentioning

confidence: 99%

The Impact of the Secondary Binding Pocket on the Pharmacology of Class A GPCRs

2022

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G-protein coupled receptors (GPCRs) are considered important therapeutic targets due to their pathophysiological significance and pharmacological relevance. Class A receptors represent the largest group of GPCRs that gives the highest number of validated drug targets. Endogenous ligands bind to the orthosteric binding pocket (OBP) embedded in the intrahelical space of the receptor. During the last 10 years, however, it has been turned out that in many receptors there is secondary binding pocket (SBP) located in the extracellular vestibule that is much less conserved. In some cases, it serves as a stable allosteric site harbouring allosteric ligands that modulate the pharmacology of orthosteric binders. In other cases it is used by bitopic compounds occupying both the OBP and SBP. In these terms, SBP binding moieties might influence the pharmacology of the bitopic ligands. Together with others, our research group showed that SBP binders contribute significantly to the affinity, selectivity, functional activity, functional selectivity and binding kinetics of bitopic ligands. Based on these observations we developed a structure-based protocol for designing bitopic compounds with desired pharmacological profile.

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“…Thus, they appeared to perform distinguishable allosteric configurations in binding affinity and/or efficacy of the "message" moiety. [108,109,122] This INTA "address" portion may have the same function as positive allosteric modulators and affect the INTA binding of the "message" site with the μOR orthosteric site. [108] Le Naour et al proved that INTA displays the least stimulation in the δOR compared to the kOR and μOR stimulation.…”

Section: Bitopic Ligandsmentioning

confidence: 99%

“…[107,108] It was identified as a novel bitopic modulator. [108][109][110] After docking, molecular dynamics (MD) and several site-directed mutagenesis studies, the epoxymorphinan moiety of NAQ which is the "message" unit was found to bind with the μOR orthosteric site and the isoquinoline ring or the "address" unit to interact with the μOR allosteric site, resembling INTA. [109] Additionally, NAQ displayed a high binding affinity of 0.55 nM to μOR with over 200-fold selectivity over the δOR and 50-fold selectivity over the kOR.…”

Section: Bitopic Ligandsmentioning

confidence: 99%

“…[108][109][110] After docking, molecular dynamics (MD) and several site-directed mutagenesis studies, the epoxymorphinan moiety of NAQ which is the "message" unit was found to bind with the μOR orthosteric site and the isoquinoline ring or the "address" unit to interact with the μOR allosteric site, resembling INTA. [109] Additionally, NAQ displayed a high binding affinity of 0.55 nM to μOR with over 200-fold selectivity over the δOR and 50-fold selectivity over the kOR. [109,111,112] NAQ exhibited antagonistic properties when compared with DAMGO (Scheme 8), a synthetic opioid peptide with high μOR-specificity, in the [ 35 S]GTPγS functional assay with μOR-expressing CHO cell lines.…”

Section: Bitopic Ligandsmentioning

confidence: 99%

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Opioid Ligands Addressing Unconventional Binding Sites and More Than One Opioid Receptor Subtype

et al. 2022

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Opioid receptors (ORs) represent one of the most significant groups of G‐protein coupled receptor (GPCR) drug targets and also act as prototypical models for GPCR function. In a constant effort to develop drugs with less side effects, and tools to explore the ORs nature and function, various (poly)pharmacological ligand design approaches have been performed. That is, besides classical ligands, a great number of bivalent ligands (i. e. aiming on two distinct OR subtypes), univalent heteromer‐selective ligands and bitopic and allosteric ligands have been synthesized for the ORs. The scope of our review is to present the most important of the aforementioned ligands, highlight their properties and exhibit the current state‐of‐the‐art pallet of promising drug candidates or useful molecular tools for the ORs.

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Computational insights into the molecular mechanisms of differentiated allosteric modulation at the mu opioid receptor by structurally similar bitopic modulators

Cited by 11 publications

References 84 publications

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

The Impact of the Secondary Binding Pocket on the Pharmacology of Class A GPCRs

Opioid Ligands Addressing Unconventional Binding Sites and More Than One Opioid Receptor Subtype

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