1. Synthesis of R-GABA Derivatives via Pd(II) Catalyzed Enantioselective C(sp 3 )-H Arylation and Virtual Validation with GABA B1 Receptor for Potential leads.
- Author
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Mohanlal S, Saha D, Pandey S, Acharya R, and Sharma NK
- Subjects
- Stereoisomerism, Catalysis, Humans, Molecular Structure, Palladium chemistry, Receptors, GABA-B chemistry, Receptors, GABA-B metabolism, gamma-Aminobutyric Acid chemistry, gamma-Aminobutyric Acid chemical synthesis, gamma-Aminobutyric Acid metabolism, Molecular Docking Simulation
- Abstract
GABA (γ-amino butyric acid) analogues like baclofen, tolibut, phenibut, etc., are well-known GABA
B1 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., (© 2024 Wiley-VCH GmbH.)- Published
- 2024
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