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return kwic search for functional out of >500 occurrences
267449 occurrences (No.100 in the rank) during 5 years in the PubMed. [cache]

67) SIGNIFICANCE STATEMENT: The cell membrane's functional role behind the duration of action of long-acting β2-adrenergic receptor (β2-AR) agonists such as salmeterol has been a subject of debate for a long time.

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PMID:34334369 DOI:10.1124/molpharm.121.000285

2021 Molecular pharmacology

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

- The drugs salmeterol, formoterol, and salbutamol constitute the frontline treatment of 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 with 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 classic and enhanced molecular dynamics 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 to be 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. SIGNIFICANCE STATEMENT: The cell membrane's functional role behind the duration of action of long-acting β2-adrenergic receptor (β2-AR) agonists such as salmeterol has been a subject of debate for a long time. This study investigated the binding and unbinding mechanisms of the three commonly used β2-AR agonists, salmeterol, formoterol, and salbutamol, using advanced simulation techniques. The obtained results offer unprecedented insights into the active role of membrane lipids in facilitating access and binding of the ligands, affecting the molecular recognition process and thus their pharmacology.

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[frequency of next (right) word to functional]

(1)24 connectivity	(20)4 brain	(39)3 material	(58)2 interactions
(2)14 magnetic	(21)4 changes	(40)3 materials	(59)2 interpretation
(3)13 and	(22)4 group	(41)3 organization	(60)2 neuroimaging
(4)13 recovery	(23)4 implications	(42)3 tasks	(61)2 organ
(5)11 role	(24)4 networks	(43)3 units	(62)2 outcome
(6)8 analyses	(25)4 training+CPM	(44)2 Threshold	(63)2 outcome,
(7)8 assays	(26)3 null	(45)2 academics,	(64)2 outcomes,
(8)8 groups	(27)3 activation	(46)2 alteration	(65)2 phenotypes
(9)8 outcomes	(28)3 activity	(47)2 antibodies	(66)2 plasticity
(10)8 roles	(29)3 annotation	(48)2 architecture	(67)2 profile
(11)8 training	(30)3 attributes	(49)2 characterization	(68)2 rating
(12)6 MRI	(31)3 capacity	(50)2 consequence	(69)2 reconstruction
(13)6 analysis	(32)3 cure	(51)2 defects	(70)2 redundancy
(14)6 properties	(33)3 effector	(52)2 differences	(71)2 relationship
(15)6 studies	(34)3 effects	(53)2 diversification	(72)2 relevance
(16)5 consequences	(35)3 enrichment	(54)2 enzymes	(73)2 selectivity
(17)5 impairment	(36)3 foods	(55)2 evaluation
(18)5 network	(37)3 impact	(56)2 groups,
(19)5 theory	(38)3 limitations	(57)2 integrity

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--- WordNet output for functional --- =>機能の, 関数の, 機能する, 機能上の, 実用的な, 機能的な Overview of adj functional The adj functional has 6 senses (first 2 from tagged texts) 1. (3) functional -- (designed for or capable of a particular function or use; "a style of writing in which every word is functional"; "functional architecture") 2. (1) functional -- (involving or affecting function rather than physiology; "functional deafness") 3. functional -- (relating to or based on function especially as opposed to structure; "the problem now is not a constitutional one; it is a functional one"; "delegates elected on a functional rather than a geographical basis") 4. functional, usable, useable, operable, operational -- (fit or ready for use or service; "the toaster was still functional even after being dropped"; "the lawnmower is a bit rusty but still usable"; "an operational aircraft"; "the dishwasher is now in working order") 5. functional -- (designed for or adapted to a function or use; "functional education selects knowledge that is concrete and usable rather than abstract and theoretical"; "functional architecture") 6. running, operative, functional, working -- ((of e.g. a machine) performing or capable of performing; "in running (or working) order"; "a functional set of brakes") --- WordNet end ---