title: Identification of Small Molecule as a High Affinity &#946;2 Agonist Promiscuously Targeting Wild and Mutated (Thr164Ile) &#946; 2 Adrenergic Receptor in the Treatment of Bronchial Asthma.
abstract: A subset of asthmatics shows refractoriness to Salbutamol owing to ADRB2 gene C.T polymorphism (rs 1800888) that substitutes Thr to Ile at the position 164 in the β2 adrenergic receptor leading to sub-optimal binding of Salbutamol. The present study aims to associate the Salbutamol (200 mcg) refractoriness with the polymorphism and select the best existing agonist with optimal binding affinity against wild and mutated receptor and further identify high affinity compound, irrespectively targeting wild and mutated receptor through virtual screening methods.
  
  
  
  Responders to Salbutamol were categorized, if percentage reversibility was greater than or equal to 12% in them, while those showing reversibility less than 12% were non-responders. The genotyping for polymorphism was performed by ARMS PCR method. Established agonists with consistent binding affinity against wild and mutated receptors formed query compound to identify high affinity molecule from Phase database through 7 point pharmacophore based screening.
  
  
  
  Polymorphism was significantly associated with non-responders (p= < 0.05) demonstrating it as a major factor of Salbutamol refractoriness. Results from Glide Docking showed that Fenoterol had highest affinity for mutated receptor and stood as second best (after Salbutamol) high affinity agonist for wild receptor among the established β2 agonists. Therefore Fenoterol formed a query molecule (7 point pharmacophore) in identification of high affinity compound for virtual screening process.
  
  
  
  Compound CACPD2011a-0001278239 identified through virtual screening against 4 million compounds in phase database was shown to irrespectively target both wild and mutated β2 adrenergic receptor with high and consistent affinity which was par greater than established β2agonists.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Bandaru
authors.forename: Mallika
authors.initials: M
authors.lastname: Alvala
authors.forename: Jyothy
authors.initials: J
authors.lastname: Akka
authors.forename: Someshwar Rao
authors.initials: SR
authors.lastname: Sagurthi
authors.forename: Anuraj
authors.initials: A
authors.lastname: Nayarisseri
authors.affiliation: Computer Aided Drug Designing and Molecular Modeling Lab, Department of Bioinformatics, Alagappa University, Karaikudi-630 003, Tamil Nadu, India. skysanjeev@gmail.com.
authors.forename: Sanjeev Kumar
authors.initials: SK
authors.lastname: Singh
authors.forename: Hema Prasad
authors.initials: HP
authors.lastname: Mundluru
mesh_terms: D001249:Asthma / Q000188:drug therapy* / Q000235:genetics; D001993:Bronchodilator Agents / Q000627:therapeutic use; D006801:Humans; D007532:Isoleucine / Q000235:genetics*; D009154:Mutation; D011110:Polymorphism, Genetic / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013912:Threonine / Q000235:genetics*
chemical_list: D001993:Bronchodilator Agents; D018343:Receptors, Adrenergic, beta-2; D054852:Small Molecule Libraries; D007532:Isoleucine; D013912:Threonine