초록
<P><B>Abstract</B><P>GABA (γ-amino butyric acid) analogues like baclofen, tolibut, phenibut, etc., are well-known GABAB1 inhibitors and pharmaceutically important drugs. However, there is a huge demand for more chiral GABA aryl analogues with promising pharmacological actions. Here, we demonstrate the chiral ligand acetyl-protected amino quinoline (APAQ) mediated enantioselective synthesis of GABAB1 inhibitor drug scaffolds from easily accessible GABA via Pd-catalyzed C(sp<SUP>3</SUP>)−H activation. The synthetic methodology shows moderate to good yields, up to 74% of <I>ee</I>. We have successfully demonstrated the deprotection and removal of the directing group to synthesize <I>R</I>-tolibut in 86% yield. Further, we employed computation to probe the binding of <I>R</I>-GABA analogues to the extracellular domain of the human GABAB1 receptor. Our Rosetta-based molecular docking calculations show better binding for four <I>R</I>-enantiomers of GABA analogues than <I>R</I>-baclofen and <I>R</I>-phenibut. In addition, we employed GROMACS MD simulations and MMPB(GB)SA calculations to identify per-residue contribution to binding free energy. Our computational results suggest analogues (3<I>R</I>)‐4‐amino‐3‐(3,4‐dimethylphenyl) butanoic acid, (3<I>R</I>)‐4‐amino‐3‐(3‐fluorophenyl) butanoic acid, (3<I>R</I>)‐3‐(4‐acetylphenyl)‐4‐aminobutanoic acid, (3<I>R</I>)‐4‐amino‐3‐(4‐methoxyphenyl) butanoic acid, and (3<I>R</I>)‐4‐amino‐3‐phenylbutanoic acid are potential leads which could be synthesized from our methodology reported here.</P></P>