Interactions between β2-Adrenoceptor Ligands and Membrane: Atomic-Level Insights from Magic-Angle Spinning NMR

Yan, Si; Shaw, Duncan; Yang, Lin-hong; Sandham, David A.; Healy, Mark P.; Reilly, John M.; Wang, Bing

doi:10.1021/acs.jmedchem.7b00205

Cited by 3 publications

(2 citation statements)

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“…S1). The specific locations and orientations of salmeterol and formoterol are in good agreement with a magicangle spinning NMR study that showed a similar depth and orientation for both the molecules (Yan et al, 2017). The difference in bilayer depths resulted in distinct orientations of their saligenin heads and markedly different interactions with the polar and alkyl lipid functional groups (Fig.…”

Section: Discussionsupporting

confidence: 86%

Membrane-Facilitated Receptor Access and Binding Mechanisms of Long-Acting β2-Adrenergic Receptor Agonists

2021

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The drugs salmeterol, formoterol, and salbutamol constitute the frontline treatment for asthma and other chronic pulmonary diseases. These drugs activate the β2-adrenergic receptors (β2-AR), a class A G-protein-coupled receptor (GPCR) and differ significantly in their clinical onset and duration of actions. According to the "microkinetic model," the long duration of action of salmeterol and formoterol compared to salbutamol were attributed, at least in part, to their high lipophilicity and increased local concentrations in the membrane near the receptor. However, the structural and molecular bases of how the lipophilic drugs reach the binding site of the receptor from the surrounding membrane remain unknown. Using a variety of classical and enhanced molecular dynamics (MD) simulation techniques, we investigated the membrane partitioning characteristics, binding, and unbinding mechanisms of the ligands. The obtained results offer remarkable insight into the functional role of membrane lipids in the ligand association process. Strikingly, salmeterol entered the binding site from the bilayer through transmembrane helices 1 and 7. The entry was preceded by membrane-facilitated rearrangement and presentation of its phenyl-alkoxy-alkyl tail as a passkey to an access route gated by F193, a residue known critical for salmeterol's affinity. Formoterol's access is through the aqueous path shared by other β2-AR agents. We observed a novel secondary path for salbutamol that is distinct from its primary route. Our study offers a mechanistic description for the membrane-facilitated access and binding of ligands to a membrane protein and establishes a groundwork for recognizing membrane lipids as an integral component in the molecular recognition process.

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Section: Discussionsupporting

confidence: 86%

Membrane-Facilitated Receptor Access and Binding Mechanisms of Long-Acting β2-Adrenergic Receptor Agonists

2021

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“…High blood pressure treatment, Angiotensin II AT1 receptor Losartan [191,192], Candesartan [193] High blood pressure treatment, β-adrenergic receptors, GPCR Acebutolol [194], Alprenolol [148,195,196], AS408 [197], Atenolol [148,196,198,199], Carazolol [200], Formoterol [201], Idacaterol and its analogs [201], Metoprolol [196], Nadolol [196], Oxprenolol [194], Pindolol [148,196], Propranolol [194,196,202], Salbutamol [199], Salmeterol [201] High blood pressure treatment Amlodipine [198,203], Lisinopril [198], Debrisoquine [132] Anticancer drug…”

Section: Application and Target Drugs And Pharmaceuticsmentioning

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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Synthesis of New 1,3-Thiazolecarbaldehydes

et al. 2017

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Interactions between β2-Adrenoceptor Ligands and Membrane: Atomic-Level Insights from Magic-Angle Spinning NMR

Cited by 3 publications

References 44 publications

Membrane-Facilitated Receptor Access and Binding Mechanisms of Long-Acting β2-Adrenergic Receptor Agonists

Membrane-Facilitated Receptor Access and Binding Mechanisms of Long-Acting β2-Adrenergic Receptor Agonists

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

Synthesis of New 1,3-Thiazolecarbaldehydes

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