Study On The Binding Mechanism Of Selective Histone Deacetylase Inhibitors

As epigenetic modification mechanisms continue to be revealed,as key regulators,the functions of histone deacetylases(HDACs)in a variety of biological processes in vivo have attracted widespread attention,and many studies have found that the abnormal expressions of HDACs are closely related to the occurrence and development of various diseases,especially cancers and neurological diseases.With the approval of histone deacetylase inhibitor(HDACsi)by the US FDA for the clinical treatment of cutaneous T-cell lymphoma and peripheral T-cell lymphoma,the development of HDACsi has become a hot topic in the field of medicinal chemistry and has shown broad development prospects.However,with the serious adverse reactions that broad-spectrum HDAC inhibitors have shown in clinical treatment,their clinical application has been limited,which has also attracted researchers to design and develop selective HDAC inhibitors.In this study,molecular dynamic(MD)simulation was applied to explore the binding mechanisms between the HDAC1,HDAC6,and HDAC8 isoforms and their corresponding selective inhibitors at the molecular level on the basis of energy analysis and conformational analysis of the equilibrium simulation trajectories,aiming to provide the theoretical basis for the rapid design of subtype selective HDACsi.1.Study on the mechanism of cyclopeptide HDAC inhibitor FK228 selectively inhibiting HDAC1.With FK228 as the representative ligand,the differences in the binding modes of FK228 in HDAC1 and HDAC6 were explored by molecular docking,molecular dynamics simulation,and amino acid energy contribution.The results showed that the two molecular dynamics simulation experiments were basically consistent.In this study,it was found that FK228 could bind stably in HDAC1,and could maintain the chelation effects between ZBG group and metal zinc ion during molecular dynamics process.However,in HDAC6-K228 system,FK228 had a large deflection at the binding site,especially the spatial displacement of the ZBG group,which caused ZBG to move away from the catalytic center and reduced the chelation effects between the ZBG and zinc ion at the bottom of HDAC6 active pocket.In addition,the sub-pocket formed in HDAC1 during MD simulation could well accommodate the Cap group,which was very important to maintain the binding conformation of FK228.2.Study on the binding modes of TSA enantiomers in HDAC1 and HDAC6.Taking TSA enantiomers as representative ligands,the initial conformations in HDAC1 and HDAC6 were obtained by molecular docking.The broad-spectrum inhibtion mechanism of R-TSA against HDAC1 and HDAC6 and the selective inhibition mechanism of S-TSA against HDAC6 were explored through molecular dynamic simulation.The conformation analysis revealed that the Cap group had different orientations in the docking conformations due to the chiral center on the molecule,and4 conservative amino acids(H134/H134,H171/H174,D169/D172,and D257/D265)and 2 non-conservative amino acids(G200/M205 and Y197/F202)were identified to play decisive roles in the difference of inhibitory activities of S-TSA between HDAC1 and HDAC6,especially the non-conservative amino acids locating on Loop3.3.Study on the selective inhibitory activity mechanism of novel HDAC6 selective inhibitor-BRD9757.At present,it is generally believed that the modification of the Cap group could improve the selective inhibitory activities of the compounds against HDAC6,but BRD9757 without Cap was reported to be a selective HDAC6 inhibitor.On the basis of this,molecular docking and MD simulation were applied to explore the binding conformations of BRD9757 in the two subtypes,and the differences in the physical and chemical properties of the active pockets of HDAC1 and HDAC6 led to the differences in the interactions of BRD9757 with key residues.The relative positions between H171 and Y296 on HDAC1 and BRD9757 changed during the MD process,which affected the interactions between the ligand and receptor and reduced the chelation effects between ZBG and zinc ion.However,in HDAC6 system,the interactions between BRD9757 and the residues at the corresponding site could be maintained during the MD process,and BRD9757 could stably bind in the active pocket of HDAC6,ensruing the chelation effects between ZBG and the zinc ion.4.Mechanism study on the effects of Cap modification on the inhibitory activity of HDAC8.HDAC8 belongs to class I HDACs,which is sensitive to Cap modification.The research systems were established by selecting small molecules with different Caps,and it was found that MET261 and TYR293 locating on the edge of the active pocket and ASP165,HIE167 and ASP254 at the bottom of the active pocket were vital for the ligands' binding through energy analysis and conformational analysis of simulated trajectories.In addition,it was also found that the molecules with a larger rigid Cap group had stronger inhibitory activities on HDAC8,which was conducive to maintaining the stable binding of the molecule and ensuring effective chelation with metal zinc ions.This study mainly focused on three representative HDAC isoforms,and the binding modes of the corresponding selective inhibitors were explored,which aimed to analyze the potential mechanisms underlying the selective inhibitory effects,providing a theoretical basis for the design of selective HDAC inhibitors.