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

Abstract

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