Vladimir I. Chupakhin

Molecular modeling of ligand–receptor interactions in GABAC receptor

A new homology model of the GABA binding site of the GABA(C) receptor was built. Natural agonist GABA and antagonist TPMPA were docked into the receptor and molecular dynamics simulation of the complexes was performed to clarify binding poses of the ligands. It was shown that orientation of the ligand is defined by salt bridges between the ligand and the arginine (Arg104) and glutamate residues (Glu194 and Glu196) of the binding site. Different behavior and binding poses for agonist and antagonist was demonstrated by molecular dynamics simulation along with differential movement of the loop C during agonist and antagonist binding. Binding orientations of the ligands revealed that main binding forces in the GABA binding site should be electrostatic ones.

Modeling and analysis of ligand-receptor interactions in the GABAC receptor

25 γ -Aminobutyric acid (GABA) is the major inhibitory transmitter in the human central nervous system. Ligands of GABA receptors may be potential drugs for treating various neurological disorders, such as Parkinson’s and Alzheimer’s diseases, sleep disorders (insomnia and narcolepsy), and epilepsy.

Ionotropic GABA receptors: modelling and design of selective ligands

Ionotropic GABAA and GABAC receptors play an important role in the operation of CNS and serve as targets for many neuroactive drugs. Using the homology modelling and molecular dynamics, the 3D models of the receptors were built and some aspects of ligand-target interactions were elucidated [1,2]. To better understand the structural factors controlling the activity and selectivity of the ligands, a series of QSAR models [3] were derived based on the Molecular Field Topology Analysis (MFTA) [4], CoMFA and Topomer CoMFA approaches. They were compared with each other as well as with the molecular modelling results. Finally, a number of potential selective ligand structures were identified by means of the virtual screening [5] from the available chemicals databases and the generated structure libraries.