In silico structure-based design of GABAB receptor agonists using a combination of docking and QSAR

Abstract

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.

Keywords: Baclofen; Docking; GABAB receptor agonists; QSAR; SAR.