Structural Analysis and Binding Modes of Benzodiazepines with Modeled GABAA Receptor Subunit Gamma-2

Activation of chloride gated GABAA receptors regulates the excitatory transmission in the epileptic brain. Positive allosteric modulation of these receptors via distinct recognition sites is the therapeutic mechanism of antiepileptic agents which prevents the hyperexcitability associated with epilepsy. These distinct sites are based on subunit composition which determines binding of various drugs like benzodiazepines, barbiturates, steroids and anesthetics. The binding of antiepileptic agents to this recognition site increases the affinity of GABAA receptor for modulating the inhibitory effects of GABAinduced chloride ion flux. In the pentameric complex structure of these receptors, the α/β interface locates the binding site of agonists and the α/γ interface forms the benzodiazepine (BZD) binding site on extracellular domain. Thus the γ subunit is shown as highly required for functional modulation of the receptor channels by benzodiazepines. The present study initiates the binding analysis of chosen benzodiazepines with the modeled GABA receptor subunit gamma-2. The extracellular domain of γ subunit of human GABAA is modeled and docking studies are performed with diazepam, flunitrazepam, and chlordiazepoxide. The results revealed the binding modes and the interacting residues of the protein with the benzodiazepines.