High performance screening, structural and molecular dynamics analysis to identify H1 inhibitors from TCM Database@Taiwan.
New-type oseltamivir-resistant H1N1 influenza viruses have been a major threat to human health since the 2009 flu pandemic. To resolve the drug resistance issue, we aimed to identify a new type of inhibitors against H1 from traditional Chinese medicine (TCM) by employing the world's largest TCM database () for virtual screening and molecular dynamics (MD). From the virtual screening results, sodium (+)-isolaricireinol-2 alpha-sulfate, sodium 3,4-dihydroxy-5-methoxybenzoic acid methyl ester-4-sulfate, sodium (E)-7-hydroxy-1,7-bis(4-hydroxyphenyl)hept-5-ene-3S-sulfonate, and 3-methoxytyramine-betaxanthin were identified as potential drug-like compounds. MD simulation of the binding poses with the key residues Asp103 and Glu83, as well as other binding site residues, identified higher numbers of hydrogen bonds than N-Acetyl-D-Glucosamine (NAG), the natural ligand of the esterase domain in H1. Ionic bonds, salt bridges, and electrostatic energy also contribute to binding stability. Key binding residues include Lys71, Glu83, Asp103, and Arg238. Structural moieties promoting H-bond or salt bridge formations at these locations greatly contribute to a stable ligand-protein complex. An available sodium atom for ionic interactions with Asp103 can further stabilize the ligands. Based on virtual screening, MD simulation, and interaction energy evaluation, TCM candidates demonstrate good potential as novel H1 inhibitors. In addition, the identified stabilizing features can provide insights for designing highly stable H1 inhibitors.
Laboratory of Computational and Systems Biology, School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan.
Su-Sen
SS
Chang
Hung-Jin
HJ
Huang
Calvin Yu-Chian
CY
Chen
D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D016208:Databases, Factual; D055808:Drug Discovery; D024882:Drug Resistance, Viral; D004365:Drugs, Chinese Herbal / Q000378:metabolism / Q000494:pharmacology*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism*; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects*; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D008516:Medicine, Chinese Traditional / Q000379:methods; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013624:Taiwan
D000998:Antiviral Agents; D004365:Drugs, Chinese Herbal; C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus