In silico Modeling of α1A-Adrenoceptor: Interaction of its Normal and Mutated Active Sites with Noradrenaline as well as its Agonist and Antagonist

Noradrenaline, like most other neurotransmitters, acts through various adrenoceptor subtypes. The structure and active site of adrenoceptors for the binding of noradrenaline were unknown, however, such information are crucial for understanding the molecular mechanism of action of neurotransmitters, including noradrenaline, in health and disease as well as for drug designing. In this in silico study, we modeled the α1A-adrenoceptor; a G protein coupled receptor and defined its active site. Further, molecular docking and interaction of noradrenaline and its agonist as well as antagonist with the so defined active site of the receptor was studied before and after in silico site directed mutation of several amino acid residues forming the active site. Our results indicate that the ARG166 is the most crucial residue for binding of noradrenaline and methoxamine to α1A-adrenoceptor and ILE178 is the most important residue for binding of prazosin to it. Thus, the observations provide new insights into the structure function relationship of α1A-adrenoceptor. A significant finding of this study is that the same residue of the active site may not be necessary for binding of a receptor with its natural ligand and its pharmacologically active known agonist and antagonist.