Assessment of Molecular Binding of Podophyllotoxin Analogues into ATPase Domain of Topoisomerase II Using Docking-MM-GB/SA Approach

Abstract

Synthetic analogues of Podophyllotoxin have been used to create efficient safer anticancer drugs. One hundred twenty six analogues using combinatorial design with structural modifications of the scaffold structure of podophyllotoxin are herein described. Molecular interaction and binding affinities with ATPase domain of human DNA Topoisomerase II (TP-II) using docking-MM-GB/SA screening are illustrated. Results showed that these analogues docked in a similar position and orientation on the ATPase domain of TP-II. A linear correlation (r2 = 0.5707) was observed between the calculated free energy of binding (FEB) and experimental IC50 for the inhibitors, suggesting that theses inhibitors bind weakly with TP-II. Three H-bonds between podophyllotoxin analogues (trans lactones) and DNA topoisomerase II were observed. The vdW energy estimated by generalized born/surface area (GB/SA) plays an important role in the binding affinity of podophyllotoxin analogues. Out of 126 derivatives, lactones tetralines were found to be the most potent in general in comparison with the non-lactones tetralines and non-lactones cyclolignans. This work addresses to modify the lactone moiety and prepare synthetic analogues with heteroatoms at different positions of the podophyllotoxin and further screening for a successful candidate drug in a computer-aided rational drug design.