New molecular insights for 4 H -1,2,4-triazole derivatives as inhibitors of tankyrase and Wnt-signaling antagonist: a molecular dynamics simulation study

Tankyrase (TNKS) enzymes remained central biotargets to treat Wnt-driven colorectal cancers. The success of Olaparib posited the druggability of PARP family enzymes depending on their role in tumor proliferation. In this work, an MD-simulation-based comparative assessment of the protein-ligand interactions using the best-docked poses of three selected compounds (two of the designed and previously synthesized molecules obtained through molecular docking and one reported TNKS inhibitor) was performed for a 500 ns period. The PDB:ID-7KKP and 3U9H were selected for TNKS1 and TNKS2, respectively. The Molecular Mechanics Generalized Born Surface Area (MM-GBSA) based binding energy data exhibited stronger binding of compound-15 (average values of -102.92 and -104.32 kcal/mol for TNKS1 and TNKS2, respectively) as compared to compound-22 (average values of -82.99 and -85.68 kcal/mol for TNKS1 and TNKS2, respectively) and the reported compound-32 (average values of -81.89 and -74.43 kcal/mol for TNKS1 and TNKS2, respectively). Compound-15 and compound-22 exhibited comparable or superior binding to both receptors forming stable complexes when compared to that of compound-32 upon examining their MD trajectories. The key contributors were hydrophobic stacking and optimum hydrogen bonding allowing these molecules to occupy the adenosine pocket by interfacing D-loop residues. The results of bond distance analysis, radius of gyration, root mean square deviation, root mean square fluctuation, snapshots at different time intervals, LUMO-HUMO energy differences, electrostatic potential calculations, and binding free energy suggested better binding efficiency for compound-15 to TNKS enzymes. The computed physicochemical and ADMET properties of compound-15 were encouraging and could be explored further for drug development.Communicated by Ramaswamy H. Sarma.