title: Traditional Chinese medicine application in HIV: an in silico study.
abstract: Viral infection by human immunodeficiency virus (HIV) requires integration of viral DNA with host DNA which involves the binding of HIV integrase (IN) with its co-factor lens epithelium-derived growth factor (LEDGF/p75). Since disrupted binding of IN with LEDGF/p75 inhibits proliferation of HIV, inhibition or denaturation of IN is a possible method for inhibiting HIV replication. D77 is a known drug with demonstrated inhibition against HIV by binding to IN. Herein, we utilized D77 as a control to screen for traditional Chinese medicine (TCM) compounds that exhibit similar atomic-level characteristics. 9-Hydroxy-(10E)-octadecenoic acid and Beauveriolide I were found to have higher Dock Scores to IN than D77 through virtual screening. Multiple linear regression (R2 = 0.9790) and support vector machine (R2 = 0.9114) models consistently predicted potential bioactivity of the TCM candidates against IN. The 40 ns molecular dynamics simulation showed that the TCM compounds fulfilled the drug-like criteria of forming stable complexes with IN. Atomic-level investigations revealed that 9-hydroxy-(10E)-octadecenoic acid bound to an important residue A:Lys173, and Beauveriolide I formed stable interactions with the core LEDGF binding site and with Asn256 of the IN binding site on LEDGF. The TCM candidates also initiated loss of α-helices that could affect the functionality of IN. Taken together, the ability of 9-hydroxy-(10E)-octadecenoic acid and Beauveriolide I to (1) form stable interactions affecting IN-LEDGF binding and (2) have predicted bioactivity against IN suggests that the TCM candidates might be potential starting structures for developing compounds that may disrupt IN-LEDGF binding. An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:40.
authors.affiliation: a Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources , China Medical University , Taichung , 40402 , Taiwan .
authors.forename: Hung-Jin
authors.initials: HJ
authors.lastname: Huang
authors.forename: Yi-Ru
authors.initials: YR
authors.lastname: Jian
authors.forename: Calvin Yu-Chian
authors.initials: CY
authors.lastname: Chen
mesh_terms: D001565:Benzoates / Q000737:chemistry*; D003198:Computer Simulation; D047630:Depsipeptides / Q000737:chemistry*; D004365:Drugs, Chinese Herbal / Q000737:chemistry*; D019427:HIV Integrase / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D008516:Medicine, Chinese Traditional; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009829:Oleic Acids / Q000737:chemistry*; D017433:Protein Structure, Secondary; D021281:Quantitative Structure-Activity Relationship; D045162:Thiazolidinediones / Q000737:chemistry*
chemical_list: C531217:4-((5-bromo-4-((2,4-dioxo-3-(2-oxo-2-phenylethyl)-1,3-thiazolidin-5-ylidene)methyl)-2-ethoxyphenoxy)methyl)benzoic acid; D001565:Benzoates; D047630:Depsipeptides; D004365:Drugs, Chinese Herbal; D019428:HIV Integrase Inhibitors; D009829:Oleic Acids; D045162:Thiazolidinediones; C013833:beauverolides; D019427:HIV Integrase