Binding modes and pharmacophoric features of muscarinic antagonism and β2 agonism (MABA) conjugates.

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.