Title:Identification of Small Molecule as a High Affinity β2 Agonist Promiscuously Targeting Wild and Mutated (Thr164Ile) β 2 Adrenergic Receptor in the Treatment of Bronchial Asthma
Volume: 22
Issue: 34
Author(s): Srinivas Bandaru, Mallika Alvala, Jyothy Akka, Someshwar Rao Sagurthi, Anuraj Nayarisseri, Sanjeev Kumar Singh and Hema Prasad Mundluru
Affiliation:
Keywords:
ADRB2 polymorphism, β2AR receptor mutation, salbutamol, fenoterol, 7 point pharmacophore modeling, virtual screening.
Abstract: Background: A subset of asthmatics shows refractoriness to Salbutamol owing
to ADRB2 gene CT 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. 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. Results: 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. Conclusion: 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.
