title: Identification of high affinity bioactive Salbutamol conformer directed against mutated (Thr164Ile) beta 2 adrenergic receptor.
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.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Bandaru
authors.forename: Geet
authors.initials: G
authors.lastname: Tiwari
authors.forename: Jyothy
authors.initials: J
authors.lastname: Akka
authors.forename: Vijaya Kumar
authors.initials: VK
authors.lastname: Marri
authors.forename: Mallika
authors.initials: M
authors.lastname: Alvala
authors.forename: Venkata Ravi
authors.initials: VR
authors.lastname: Gutlapalli
authors.forename: Anuraj
authors.initials: A
authors.lastname: Nayarisseri
authors.affiliation: Bioinformatics Research Laboratory, Eminent Biosciences, Vijaynagar, Indore - 452010, Madhya Pradesh, India. anuraj@eminentbio.com.
authors.forename: Hema Prasad
authors.initials: HP
authors.lastname: Mundluru
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry* / Q000627:therapeutic use; D000328:Adult; D000420:Albuterol / Q000031:analogs & derivatives*; D019943:Amino Acid Substitution; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000737:chemistry* / Q000627:therapeutic use; D015195:Drug Design; D055808:Drug Discovery; D005260:Female; D005541:Forced Expiratory Volume; D015870:Gene Expression; D005838:Genotype; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D008875:Middle Aged; D062105:Molecular Docking Simulation; D009154:Mutation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry* / Q000235:genetics; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: C553443:ADRB2 protein, human; D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D018343:Receptors, Adrenergic, beta-2; D000420:Albuterol