In silico studies on potential TNKS inhibitors: a combination of pharmacophore and 3D-QSAR modelling, virtual screening, molecular docking and molecular dynamics

Maladjustment of the Wnt-signalling pathway can lead to a variety of cancers. Axin can be expressed stably through the Tankyrases (TNKS) inhibitor, thus inducing the degradation of β-catenin, antagonizing the Wnt-signalling pathway and consequently inhibiting tumour growth. Thus, TNKS has become a hot research target for anticancer drugs, and a systematic study of tetrazoloquinoxaline analogues as TNKS inhibitors is of considerable value. In this paper, three-dimensional (3D)-quantitative structure–activity relationship (QSAR), molecular docking and DISCOtech were applied to study a series of tetrazoloquinoxaline and establish a good comparative molecular field analysis (CoMFA) (q² = 0.701, r² = 0.968 and r_pred² = 0.754), comparative molecular similarity index analysis (CoMSIA) (q² = 0.572, r² = 0.991 and r_pred² = 0.721) and Topomer CoMFA (q² = 0.692, r² = 0.979 and r_pred² = 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 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. These results provide favourable theoretical guidance for the development of novel TNKS inhibitors.