Cell-based assays and molecular dynamics analysis of a boron-containing agonist with different profiles of binding to human and guinea pig beta2 adrenoceptors
The design of beta2 adrenoceptor (β 2 AR) agonists is attractive because of their wide-ranging applications in medicine, and the details of agonist interactions with β 2 AR are interesting because it is considered a prototype for G-protein coupled receptors. Preclinical studies for agonist developme...
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Published in | European biophysics journal Vol. 48; no. 1; pp. 83 - 97 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Cham
Springer International Publishing
01.01.2019
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | The design of beta2 adrenoceptor (β
2
AR) agonists is attractive because of their wide-ranging applications in medicine, and the details of agonist interactions with β
2
AR are interesting because it is considered a prototype for G-protein coupled receptors. Preclinical studies for agonist development have involved biological assays with guinea pigs due to a similar physiology to humans. Boron-containing Albuterol derivatives (BCADs) designed as bronchodilators have improved potency and efficacy compared with their boron-free precursor on guinea pig β
2
ARs (gpβ
2
ARs), and two of the BCADs (BR-AEA and boronterol) conserve these features on cells expressing human β
2
ARs (hβ
2
ARs). The aim of this study was to test the BCAD Politerol on gpβ
2
ARs and hβ
2
ARs in vitro and in silico. Politerol displayed higher potency and efficacy on gpβ
2
AR than on hβ
2
AR in experimental assays, possible explanations are provided based on molecular modeling, and molecular dynamics simulations of about 0.25 µs were performed for the free and bound states adding up to 2 µs in total. There were slight differences, particularly in the role of the boron atom, in the interactions of Politerol with gpβ
2
ARs and hβ
2
ARs, affecting movements of transmembrane domains 5–7, known to be pivotal in receptor activation. These findings could be instrumental in the design of compounds selective for hβ
2
ARs. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0175-7571 1432-1017 |
DOI: | 10.1007/s00249-018-1336-9 |