Structure-activity Relationship And Virtual Screening Of Anti-tumor Tetrazoquinoxaline TNKS Inhibitors

Tankyrase TNKS is an important target for the treatment of cancer.Inhibiting the expression of TNKS is beneficial to stabilize Axin and inducing the degradation of?-catenin,antagonizing the Wnt signalling pathway and consequently inhibiting tumour growth.Aiming at the inhibitors of the TNKS,systematic theoretical studies have been carried out using computer aided drug molecular design,CADD.In this paper,TNKS inhibitors were studied by DISCOtech,molecular docking,molecular dynamic simulation,virtual screening and 3D-QSAR methods.In this paper,3D-QSAR,molecular docking and DISCOtech were applied to study a series of tetrazoloquinoxaline and establish good CoMFA(q²=0.701,r²=0.968 and r²_pred=0.754),CoMSIA 12(q²=0.572,r²=0.991 and r²_pred=0.721)and Topomer CoMFA?q²=0.692,r²=0.979 and rpred²=0.532?models,which offer high predictability.The effect of steric hindrance,electrostatic interaction,hydrophobic interaction and hydrogen bonding acceptor of the molecular group on molecular activity was revealed through contour map.Molecular docking revealed the binding pattern between acceptor and ligand and determined that the effect of hydrogen bond interaction between the inhibitor and the residue GLY1032 was critical to the molecular activity.The pharmacophore features were consistent with the contour map and the molecular docking result.Through filtering the ZINC database?including 8777 micro-molecule structures?,we obtained candidate compounds TS1 and TS2,which exhibit a novel scaffold structure and potential inhibitory activities against TNKS.Molecular docking and molecular dynamics studies of compounds TS1 and TS2 were used to confirm that the binding interaction between ligand and receptor is mainly hydrogen bonding between the compound and residue GLY1032,as well as the hydrophobic interaction with TYR1071.Molecular Dynamics studies showed that compounds TS1 and TS2 can stably bind with receptors.The newly screened candidate compounds TS1 and TS2were identified as having good potential for inhibiting TNKS activity and intensive research.These results provide favourable theoretical guidance for the development of novel TNKS inhibitors.