Virtual Screening And Validation Of Histone Deacetylase Inhibitors Based On Computer Aided Drug Design

Histone deacetylases(HDACs)are a kind of protease,which play an important role in the structural modification of chromosome and the regulation of gene expression,and are closely related to the occurrence and development of tumor.Therefore,histone deacetylase inhibitors(HDACIs)as a new generation of targeted antitumor drugs,have become a hot spot in the field of drug research.Computer aided drug design(CADD)computes the interaction between drugs and receptor biomacromolecules by computer simulation,and designs and optimizes the lead compounds,which greatly accelerates the process of discovery of new drugs and has become a drug normal method.Based on the method of computer virtual screening,this paper proposes a new hierarchical HDACI computer virtual screening process,which is used for HDACIs screening and experimental verification,and the details are as follows: First of all,the virtual screening pharmacophore based virtual screening using the GALAHAD module of SYBYL-X2.0 software,with a small molecular training set of 7 molecules to form the pharmacophore model,then UNITY searched from the Chembridge database of about 650 thousand small molecules,finally got 5518 small molecules.Secondly,using GOLD 5.2 molecular docking screening,5518 received small molecule were docked to the protein receptor 1T69,to observe the difference between the conformation of the ligand and the conformation,using GOLDMine module to select the scoring function within a certain range of small molecules.At the same time,50 small molecules with large structural differences were selected by cluster analysis.Finally,in order to better determine the binding of molecules and receptors,we used molecular dynamics(MD)simulation to study the dynamics of the system,GROMACS software was used to carry out the virtual screening of molecular dynamics,and GROMACS was used to stretch the ligand molecule from the receptor binding site,and then calculating PMF curves of 50 small molecules with their △Gbind,The final choice of 30 small molecules for the inhibition of enzyme activity in vitro,of which 5 small molecules had the inhibitory activity of HDACs.The computer virtual screening process proposed in this paper combines molecular dynamics simulation with traditional pharmacophore screening and molecular docking to study the relationship between the structure and properties of molecular or molecular systems in a simulated solvent environment,which makes up the traditional virtual method insufficient.Through the establishment of the virtual screening process,the final screening of five new histone deacetylase inhibitor molecules,proved the effectiveness of this screening process.The computer virtual screening method proposed in this paper has important reference value for the screening of other active compounds.