Drug Design for Neuropathic Pain Regulation from Traditional Chinese Medicine

• Published in: Scientific reports 2013-01, Vol.3 (1), p.844-844, Article 844
• Main Authors: Tou, Weng Ieong, Chang, Su-Sen, Lee, Cheng-Chun, Chen, Calvin Yu-Chian
• Format: Article
• Language: English
• Subjects: 631/114; 631/378/340; 631/57; 692/308; Alkenes - chemistry; Alkenes - therapeutic use; Amides - chemistry; Amides - therapeutic use; Amino Acid Sequence; Anandamide; Animals; Antagonists; Benzodioxoles - chemistry; Benzodioxoles - therapeutic use; Binding Sites; Biological activity; Chinese medicine; Drug Design; Drug development; Fatty Acid-Binding Proteins - antagonists & inhibitors; Fatty Acid-Binding Proteins - metabolism; Fatty-acid amide hydrolase; Heterocyclic Compounds, 2-Ring - chemistry; Heterocyclic Compounds, 2-Ring - therapeutic use; Humanities and Social Sciences; Humans; Hydrolysis; Ligands; Linear Models; Medicine, Chinese Traditional; Molecular Docking Simulation; Molecular dynamics; Molecular Sequence Data; multidisciplinary; Neuralgia; Neuralgia - drug therapy; Pain; Protein structure; Protein Structure, Secondary; Protein Structure, Tertiary; Quantitative Structure-Activity Relationship; Rats; Science; Secondary structure; Sequence Alignment; Support Vector Machine; Traditional Chinese medicine; Vibrations
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep00844

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.