title: Drug design for neuropathic pain regulation from traditional Chinese medicine.
abstract: FAAH-like anandamide transporter (FLAT) regulates anandamide transport for hydrolysis and may be an attractive drug target for pain regulation. We aimed to discover potential FLAT antagonists from traditional Chinese medicine (TCM) using virtual screening, ligand-based drug design and molecular dynamics simulation (MD). Guineensine and Retrofractamide A exhibited high Dock Scores in FLAT. Consensus from multiple linear regression (MLR; R(2) = 08973) and support vector machine (SVM; R(2) = 0.7988) showed similar bioactivities for Guineensine and the FAAH-1 inhibitor (9Z)-1-(5-pyridin-2-yl-1,3,4-oxadiazol-2-yl)octadec-9-en-1-one. Contour of Guineensine to CoMFA and CoMSIA features also imply bioactivity. MD revealed shake or vibration in the secondary structure of FLAT complexed with Guineensine and (9Z)-1-(5-pyridin-2-yl-1,3,4-oxadiazol-2-yl)octadec-9-en-1-one. Ligand movement might contribute to protein changes leading to vibration patterns. Violent vibrations leading to an overall decrease in FLAT function could be the underlying mechanism for Guineensine. Here we suggest Guineensine as a drug-like compound with potential application in relieving neuropathic pain by inhibiting FLAT.
authors: School of Medicine, College of Medicine, China Medical University, Taichung, 40402, Taiwan.
authors: Weng Ieong
authors: WI
authors: Tou
authors: Su-Sen
authors: SS
authors: Chang
authors: Cheng-Chun
authors: CC
authors: Lee
authors: Calvin Yu-Chian
authors: CY
authors: Chen
mesh_terms: D000475:Alkenes / Q000737:chemistry* / Q000627:therapeutic use; D000577:Amides / Q000737:chemistry* / Q000627:therapeutic use; D000595:Amino Acid Sequence; D000818:Animals; D052117:Benzodioxoles / Q000737:chemistry* / Q000627:therapeutic use; D001665:Binding Sites; D015195:Drug Design; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D016014:Linear Models; D008516:Medicine, Chinese Traditional; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009437:Neuralgia / Q000188:drug therapy; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D016415:Sequence Alignment; D060388:Support Vector Machine
chemical_list: D000475:Alkenes; D000577:Amides; D052117:Benzodioxoles; C493319:FABP1 protein, human; D050556:Fatty Acid-Binding Proteins; D006574:Heterocyclic Compounds, 2-Ring; C492480:guineensine; C454279:retrofractamide A
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