In silico structure‐based design of GABA B receptor agonists using a combination of docking and QSAR

The study of γ‐aminobutyric acid B receptor ( GABA B ) activation is of great interest for several brain disorders. The search of new GABA B receptor agonists has been carried out by many research groups. As a result, Baclofen has become the prototypical GABA B receptor agonist. However, several attempts have been made to modify its structure to generate derivatives with improved activity. In this work, we carried out a theoretical and computational study for a wide range of GABA B receptor agonists reported in the literature. Molecular docking and QSAR techniques were combined by using the interaction energies of the agonists with the key residues of GABA B receptor, as molecular descriptors for the QSAR construction. The resulting mathematical model suggests that the activity of GABA B receptor agonists is influenced by three factors: their shape and molecular size (PW5 and PJI2), their constitutional features ( E LUMO and T(N…O)) and the energy interaction with GABA B receptor ( E TRP278 ). This model was validated by the QUIK , REDUNDANCY and OVERFITTING rules, and its predicted ability was tasted by the Q LOO , Q ASYM , R 0 2 and r m 2 rules. Finally, six new compounds are proposed ( 35 – 40 ) with high potential to be used as GABA B receptor agonists.