Abstract:
:Salbutamol forms an important and widely administered β2 agonist prescribed in the symptomatic treatment of bronchial asthma. Unfortunately, a subset of patients show refractoriness to it owing to ADRB2 gene variant (rs 1800888). The variant substitutes Thr to Ile at the position 164 in the β2 adrenergic receptor leading to sub-optimal binding of agonists. The present study aims to associate the Salbutamol response with the variant and select the bioactive conformer of Sabutamol with optimal binding affinity against mutated receptor by in silico approaches. To assess bronchodilator response spirometry was performed before and 15 min after Salbutamol (200 mcg) inhalation. Responders to Salbutamol were categorized if percentage reversibility was greater than or equal to 12%, while those showing FEV₁ reversibility less than 12% were classified as non-responders. Among the 344 subjects screened, 238 were responders and 106 were non-responders. The frequency of mutant allele "T" was significantly higher in case of non-responders (p < 0.05). In silico process involved generation of Salbutamol conformer ensembles supported by systematic search algorithm. 4369 conformers were generated of which only 1882 were considered bioactive conformers (threshold RMSD≤1 in reference to normalized structure of salbutamol). All the bioactive conformers were evaluated for the binding affinity against (Thr164 Ile) receptor through MolDock aided docking algorithm. One of the bioactive conformer (P.E. = -57.0038, RMSD = 0.6) demonstrated 1.54 folds greater affinity than the normal Salbutamol in the mutated receptor. The conformer identified in the present study may be put to pharmacodynamic and pharmacokinetic studies in future ahead.
journal_name
Curr Top Med Chemjournal_title
Current topics in medicinal chemistryauthors
Bandaru S,Tiwari G,Akka J,Marri VK,Alvala M,Gutlapalli VR,Nayarisseri A,Mundluru HPdoi
10.2174/1568026615666150112113040subject
Has Abstractpub_date
2015-01-01 00:00:00pages
50-6issue
1eissn
1568-0266issn
1873-4294pii
CTMC-EPUB-64454journal_volume
15pub_type
杂志文章abstract::The field of quantitative structure activity relationships (QSAR) has evolved into an integral tool for pharmaceutical discovery. It is presently an accessible technology, as can be shown by the number papers which are easily found through PubMed literature searches. At one level, QSAR is used routinely and invisibly ...
journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章,评审
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journal_title:Current topics in medicinal chemistry
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journal_title:Current topics in medicinal chemistry
pub_type: 杂志文章
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journal_title:Current topics in medicinal chemistry
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journal_title:Current topics in medicinal chemistry
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journal_title:Current topics in medicinal chemistry
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journal_title:Current topics in medicinal chemistry
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journal_title:Current topics in medicinal chemistry
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journal_title:Current topics in medicinal chemistry
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journal_title:Current topics in medicinal chemistry
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journal_title:Current topics in medicinal chemistry
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