Study On The Construction And Application Of Molecular Modeling For HDAC And PP1 Inhibitors

Nowadays,computer-aided drug design(CADD),one of the conventional methods for rational drug design,is frequently used in novel drug research.CADD greatly accelerate efficiency of drug development.Cancer and cardiovascular disease,serious threatens to human life,have become a current event in the field of medicine.Histone deacetylase(HDAC)and Protein phosphatase 1 have emerged as promising target for tumor and cardiovascular disease,respectively.In this thesis,HD AC inhibitors and PP1 inhibitors were studied using a combination of various CADD methods.Ligand-based drug design methods were used to built pharmacophore modeling and 3D-QSAR modeling.The results of validations demonstrated their preferable reliability and good predictive ability.Receptor-based drug design methods were used to select the target protein and appropriate molecular docking module.Then,the Drugbank database was screened by integrating the pharmacophore,3D-QSAR modeling and molecular docking.Two hit molecules(DB03889 and DB02830)were obtained with novel scaffolds as a result.Finally,the binding affinity of hit DB03889,DB02830 and reference ligand(Trichostatin A)was confirmed using molecular dynamics(MD)simulation.The analysis indicated that these compunds could interact with HDAC.The obtained hit DB03889 possessed higher binding affinity with receptor than Trichostatin A,potential leading compound for the novel scoffld of HDAC inhibitors was provided.Furthermore,some HDAC residues were suggested played a key role in the formation of protein-ligand complex,which were constituted to the active site.The resarech is meaningful for the further modification of HDAC inhibitors.It could be concluded that our protocol of virtual screening is suitable for popularization and application.7 X-ray crystal structures of PP1 bound with ligands which came from Homo sapiens in the RCSB Protein Data Bank(PDB),were used for protein-ligand interaction fingerprint(PLIF)analysis.Based on PLIF analysis,a pharmacophore hypothesis was constructed.The predicted pharmacophore query was also validated by an enrichment factor using decoy set.The generated model could find active molecules from decoy molecules accurately.The integrated in silico protocol,including interaction-based pharmacophore model and molecular docking,was performed to screen TCM database@Taiwan and Biopurify phytochemicals database.Five compounds with novel scaffolds were chosen for inhibitory activity assay and ZINC43060554 showed strongly inhibitory activity with IC50 values of 26.78?M.In order to explain the mechanism of PP1 inhibitors,molecular docking was carried out for a series of derivatives of cantharidin from synthesis study.The results indicated that the carboxy groups and the oxygen atom on bridge ring of cantharidin derivatives involved in metal ion coordination,hydrogen bonds and salt bridge in protein.Finally,through the Langendroff non-recirculating mode,only potent PP1 inhibitors could increase the left ventricular contractivity.The resarech is meaningful for rational design of PP1 inhibitors with high affinity and anti-heart failure drugs.