title: Discovery of novel insomnia leads from screening traditional Chinese medicine database.
abstract: Insomnia is a prominent modern disease that affects an increasing population. Undesirable side effects of commercial drugs highlight the need to develop novel insomnia drugs. Virtual screening of traditional chinese medicine Database@Taiwan (TCM Database@Taiwan) identified 2-O-Caffeoyl tartaric acid (1), 2-O-Feruloyl tartaric acid (2), and Mumefural (3) as potential agonists for both gamma-amino butyric acid (GABA) or benzodiazepine (BZ) binding sites. The TCM candidates exhibited higher affinity than GABA and Zolpidem, a phenomenon that could be attributed to higher quantity of stabilizing H-bonds. Efficacy profiles using support vector machines and pharmacophore contour also suggest drug potential of the TCM candidates. Fragments added to the de novo derivatives 3a, 3b, 3c for GABA binding site, and 1a, 2a, and 3d for BZ binding site contributed to new binding sites and structural stability, further optimizing binding to GABA or BZ binding sites. Increased opening of the ion channel by candidate ligands provide strong support for their potential biological functions. The dual binding properties of the TCM candidates present a unique opportunity to develop twin-targeting drugs with less side effects. Derivative structures can be used as starting points for developing high affinity GABAA receptor agonists with specificity towards GABA binding site and BZ binding site.
authors.affiliation: a Department of Biomedical Informatics , Asia University , Taichung , 41354 , Taiwan .
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Chen
authors.forename: Su-sen
authors.initials: SS
authors.lastname: Chang
authors.forename: Yueh-Chiu
authors.initials: YC
authors.lastname: Chan
authors.forename: Calvin Yu-Chian
authors.initials: CY
authors.lastname: Chen
mesh_terms: D001665:Binding Sites; D002109:Caffeic Acids / Q000737:chemistry*; D019343:Citric Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D003373:Coumaric Acids / Q000737:chemistry*; D062126:Databases, Chemical; D004365:Drugs, Chinese Herbal / Q000737:chemistry*; D005663:Furans / Q000737:chemistry*; D018755:GABA Agonists / Q000737:chemistry*; D006801:Humans; D008516:Medicine, Chinese Traditional; D056004:Molecular Dynamics Simulation; D011963:Receptors, GABA-A / Q000737:chemistry*; D007319:Sleep Initiation and Maintenance Disorders / Q000628:therapy*; D013644:Tartrates / Q000737:chemistry*; D005680:gamma-Aminobutyric Acid / Q000737:chemistry
chemical_list: D002109:Caffeic Acids; D003373:Coumaric Acids; D004365:Drugs, Chinese Herbal; D005663:Furans; D018755:GABA Agonists; D011963:Receptors, GABA-A; D013644:Tartrates; C474564:caffeoyl tartaric acid; C474565:feruloyl tartaric acid; C412144:mumefural; D019343:Citric Acid; D005680:gamma-Aminobutyric Acid