Comparative conformational variation and flexibility analysis of binding site D-loop and its importance in designing of potential tankyrases inhibitors

摘要

The principle point of this study is to know the dynamics of D-loop affecting the inhibitory action of tankyrase inhibitors (TNKSIs). The knowledge of D-loop conformational variations, flexibility analysis and its significance in the binding of TNKSIs has not been explored earlier. This study at first focused on observing the conformational changes of D-loop in tankyrases crystal structures by overlapping of D-loop residues. To achieve this, relative residue fluctuation profile and molecular mechanics with generalised born surface area solvation (MM/GBSA) free energy calculations were performed to expose the more prominent binding strength of strong inhibitors and selectivity compared with other respective site inhibitors. Molecular dynamics simulation search revealed that residue fluctuation profile of D-loop of TNKSs affects the binding potential of inhibitors. Thus, conformational changes in the D-loop affected by inhibitors can be used to screen the potent TNKSIs. The molecular docking, D-loop flexibility analysis, molecular dynamics and MM/GBSA binding energy calculations were carried out.