Affiliation:
1. School of Chemical Sciences National Institute of Science Education and Research, Bhubaneswar Jatni 752050
2. Homi Bhabha National Institute (HBNI) Training School Complex, Anushaktinagar Mumbai 400094 India
3. School of Biological Sciences National Institute of Science Education and Research, Bhubaneswar Jatni 752050
Abstract
AbstractGABA (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(sp3)−H activation. The synthetic methodology shows moderate to good yields, up to 74% of ee. We have successfully demonstrated the deprotection and removal of the directing group to synthesize R–tolibut in 86% yield. Further, we employed computation to probe the binding of R–GABA analogues to the extracellular domain of the human GABAB1 receptor. Our Rosetta–based molecular docking calculations show better binding for four R–enantiomers of GABA analogues than R–baclofen and R–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 (3R)‐4‐amino‐3‐(3,4‐dimethylphenyl) butanoic acid, (3R)‐4‐amino‐3‐(3‐fluorophenyl) butanoic acid, (3R)‐3‐(4‐acetylphenyl)‐4‐aminobutanoic acid, (3R)‐4‐amino‐3‐(4‐methoxyphenyl) butanoic acid, and (3R)‐4‐amino‐3‐phenylbutanoic acid are potential leads which could be synthesized from our methodology reported here.
Funder
Department of Atomic Energy, Government of India
Cited by
1 articles.
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