kwic
observed
observed
right
off
ON
293
1
100
500
strict
ELIZA cgi-bash version rev. 1.91
- Medical English LInking keywords finder for the PubMed Zipped Archive (ELIZA) -
return
kwic search for observed out of >500 occurrences
392826 occurrences (No.45 in the rank) during 5 years in the PubMed. [no cache] 500 found
--- ABSTRACT ---
--- ABSTRACT END ---
[frequency of next (right) word to observed]
392826 occurrences (No.45 in the rank) during 5 years in the PubMed. [no cache] 500 found
| 293) We observed a novel secondary path for salbutamol that is distinct from its primary route. |
| 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. |
[
right
kwic]
(1)119  in |
(11)6 a |
(21)4 when |
(31)2 associations |
| (2)35 *null* | (12)6 an |
(22)3 among |
(32)2 differences |
| (3)35 for |
(13)6 the |
(23)3 data |
(33)2 due |
| (4)23 that |
(14)5 as |
(24)3 enhanced |
(34)2 enzyme |
| (5)23 with |
(15)5 at |
(25)3 increased |
(35)2 increase |
| (6)18 between |
(16)4 on |
(26)3 interim |
(36)2 reading |
| (7)10 by |
(17)4 only |
(27)3 previously |
(37)2 significant |
| (8)9 and |
(18)4 to |
(28)3 significantly |
|
| (9)9 during |
(19)4 under |
(29)2 (p |
|
| (10)7 after |
(20)4 using |
(30)2 THC |
add keyword
--- WordNet output for observed ---