Traditional Chinese medicine application in HIV: an in silico study.

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.

Investigation of silent information regulator 1 (Sirt1) agonists from Traditional Chinese Medicine.

Silent information regulator 1 (Sirt1), a class III nicotinamide adenine dinucleotide dependent histone deacetylases, is important in cardioprotection, neuroprotection, metabolic disease, calorie restriction, and diseases associated with aging. Traditional Chinese Medicine (TCM) compounds from TCM Database@Taiwan ( http://tcm.cmu.edu.tw/ ) were employed for screening potent Sirt1 agonists, and molecular dynamics (MD) simulation was implemented to simulate ligand optimum docking poses and protein structure under dynamic conditions. TCM compounds such as (S)-tryptophan-betaxanthin, 5-O-feruloylquinic acid, and RosA exhibited good binding affinity across different computational methods, and their drug-like potential were validated by MD simulation. Docking poses indicate that the carboxylic group of the three candidates generated H-bonds with residues in the protein chain from Ser441 to Lys444 and formed H-bond, π-cation interactions, or hydrophobic contacts with Phe297 and key active residue, His363. During MD, stable π-cation interactions with residues Phe273 or Arg274 were formed by (S)-tryptophan-betaxanthin and RosA. All candidates were anchored to His363 by stable π- or H-bonds. Hence, we propose (S)-tryptophan-betaxanthin, 5-O-feruloylquinic acid, and RosA as potential lead compounds that can be further tested in drug development process for diseases associated with aging An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:28.