The active ingredients of Huanglian Jiedu Decoction in treating COVID- 19 based on network pharmacology, molecular docking and molecular dynamics simulation

Objective:To explore the active ingredients of Huanglian Jiedu Decoction(HLJD)for the treatment of COVID-19 and to further verify the combination mode.Methods:The TCMSP database was used to search for HLJD active ingredients and targets.COVID-19 targets were collected from GeneCards,DisGeNET and OMIM databases.Material-active-ingredients-targets(gene)network and targets protein-protein interaction network were constructed using Cytoscape 3.8.0 and the STRING database.GO functional enrichment analysis and KEGG pathway enrichment analysis of core targets were performed using R software.Cytoscape 3.8.0 was used to build“compound-targets-pathways”to predict HLJD mechanisms,and active ingredients were used as ligands to molecularly dock with SARS-CoV-23CL hydrolase,Spike glycoprotein and ACE2.The binding energy was calculated by molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area method,and intermolecular interactions and the contribution of each residue to the binding free energy were analyzed.Results:Four medicinal materials,66 compounds and 219 targets were identified.It is found that the Protein-Protein Interaction core network contained 35 HLJD key targets proteins for COVID-19 treatment.705 GO functional enrichment entries(P<0.05)were produced;while KEGG pathway enrichment analysis identified 142 pathways(P<0.05)involving the Tumor Necrosis Factor signaling pathway and Interleukin-17 signaling pathway,etc.The binding energies of Kihadanin A,Palmidin A,Obacunone and Hispidone are much smaller than those of the currently reported clinical drugs with anti-SARS-CoV-2 drugs.The results of the binding energy indicate that van der Waals force is the main driving force for enzyme-substrate combination,whereas the electrostatic interaction and non-polar solvents contribute less.Conclusion:The“multi-component-multi-targets-multi-pathway”synergy of HLJD,which binds to SARSCoV-23CL hydrolase,Spike glycoprotein and ACE2,can act on targets Heat Shock Protein 90 Alpha Family Class A Member 1,Adrenoceptor Beta 2,Checkpoint Kinase 1,Peroxisome Proliferator-Activated Receptor Gamma and Mitogen-activated protein kinase 14 to regulate multiple signal pathways,and it may have a therapeutic effect on COVID-19.

Palladium-catalyzed oxidative homocoupling of 2-arylquinazolinones

Pd-catalyzed oxidative homocoupling of 2-arylquinazolinones was successfully developed for the direct construction of biaryls via C—H bond activation.New well-defined structure that possessed two quinazolinone units was obtained with high efficiency and atomic economy.The protocols offer an efficient approach to the synthetically useful and functionalized biaryls in good yields using quinazolinone as a directing group.