| Summary: | 碩士 === 亞洲大學 === 生物與醫學資訊學系碩士在職專班 === 100 === Insomnia is a modern disease that affects an increasing population. Strong and undesirable side effects of commercial drugs highlight the need to develop novel insomnia drugs. Traditional Chinese Medicine Database@Taiwan (TCM Database@Taiwan) was employed to screen for agonists of γ-amino butyric acid type A receptor (GABAA R) using modeled GABA or benzodiazepine (BZ) binding sites. Candidates 2-O-Caffeoyl tartaric acid, 2-O-feruloyl tartaric acid, and mumefural had Dock Scores higher than GABA and Zolpidem in both sites, respectively. De novo evolution further increased affinity of ligands to the binding sites. The top three de novo candidates for GABA binding sites were Mumefural Evo-1, Mumefural Evo-5, Mumefural Evo-2 and that for BZ binding site were 2-O-Caffeoyl tartaric acid Evo-B, 2-O-Feruloyl tartaric acid Evo-J, and Mumefural Evo-A. De novo candidates formed more stabilizing interactions, including hydrogen bonds and hydrophobic interactions, during docking than their parent compounds. From 20 ns molecular dynamics simulation, we conclude that Tyr309, Arg499, Arg517 and Arg552 are key residues for GABA binding site, and Arg799 and Arg852 are key residues for BZ binding site. Torsion fluctuations were greatly reduced in de novo candidates, possibly due to increased interactions and structural integrity enabled by the added fragments. LigandPath analysis shows that all ligands have multiple entry and exit paths to and from the binding sites. All TCM ligands contoured to pharmacophore features of GABA or BZ binding site, implying drug-like effects. Structurally, the carboxyl group is critical for stable binding with GABA or BZ binding sites. Based on this study, TCM candidates 2-O-Caffeoyl tartaric acid, 2-O-feruloyl tartaric acid, and mumefural are potential candidates for GABAA R activation. De novo candidates from these parent compounds are also potent compounds for developing novel insomnia drugs.
|
|---|
