β2 agonists and anticholinergics are two major classes of bronchodilators which form first line of drugs recommended
in symptomatic treatment of asthma and COPD. Combinational therapy involving β agonists and anticholinergics
prove more effective in treating airway disease than use of either agent alone. In present investigation, binding modes
of Muscarinic Antagonism and β 2 Agonism (MABA) conjugates designed by Lyn et al. were revealed on structural
grounds adopting molecular docking techniques. The conjugates tether β 2 motif onto M3 motif which makes it a single
molecule that acts as both β 2 agonist and antimuscarinic agent. Series of conjugates were docked against β 2 adrenergic
receptor and modeled M3 muscarinic acetylcholine receptor and pharmacophoric features were identified. Upon screening
the conjugates on the basis of receptor ligand free energy, hydrogen bonding and internal electrostatic interaction, conjugate
11 demonstrated superior interactions with the receptors compared to remaining conjugates in the series. While, in vitro
results and in silico outcomes are in agreement to reveal that conjugate 11 to possess best pharmacological profile,
binding modes obtained in docking can be utilized to design new conjugates with improved biological activity. A close
study of receptor residues in binding site and atoms, groups and substructures of conjugates may be used to develop favourable
secondary valence forces towards receptor-ligand interactions.
Keywords: Chronic obstructive pulmonary disease (COPD), asthma, bronchodilators, muscarinic antagonism and β 2 agonism
(MABA) conjugates, comparative modeling, molecular docking, pharmacophore identification.
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