Computational Evaluation of a Novel GABA_B Receptor Agonist through Molecular Docking, Molecular Dynamics and Binding Free Energy Calculations

Gamma-aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system. This molecule, where it exerts its agonistic activity by interacting with the orthosteric binding site located in the extracellular N-terminal domain, known as the Venus Flytrap (VFT) domain. This binding site is also targeted by compounds such as the agonist baclofen and the antagonist S-2-hydroxybaclofen.

It is important to note that, to date, no other GABA_B receptor agonists have been approved by the FDA. Therefore, the search for new molecules capable of acting as GABA_B receptor agonists is of particular interest, since baclofen may induce tolerance and exhibits limited ability to cross the blood-brain barrier.

In the present study, the affinity of a baclofen analogue, rac-4-amino-4-(4-methoxyphenyl)butanoic acid, toward the GABA_B receptor was evaluated through molecular docking studies. The results showed that this analogue exhibited a binding affinity of −9.05 kcal/mol, which was more favorable than that obtained for baclofen (−8.64 kcal/mol). Moreover, the compound established a hydrogen-bond network with residues Ser130, Gly151, Ser153, Tyr250, and Glu349, some of which are also involved in the interactions observed for the reference agonist.

Subsequently, molecular dynamics simulations (100 ns) confirmed the stability of the drug–receptor complex, with RMSD values below 1.5 Å. The binding free energy was −104 kcal/mol, comparable to that of endogenous GABA (−122 kcal/mol), suggesting that rac-4-amino-4-(4-methoxyphenyl)butanoic acid is a promising GABA_B receptor agonist candidate.