Pharmacoinformatics analysis of merbarone binding site in human topoisomerase IIα

Merbarone is a derivative of thiobarbituric acid, possessing catalytic inhibitory potential against human topoisomerase IIα (hTopoIIα). Merbarone was reported to inhibit DNA cleavage by hTopoIIα. It is important to understand the molecular mechanism of hTopoIIα inhibition by merbarone, as these details guide the rational design of new ligands. In this work, a systematic pharmacoinformatics analysis has been reported to analyze the merbarone-hTopoIIα interactions and to identify merbarone analogs as potential hTopoIIα inhibitors. The reported crystal structure of hTopoIIα-DNA complex (PDB ID: 4FM9) is not suitable for analyzing the merbarone-binding domain, because it is a biological assembly of hTopoIIα in C-gate open conformation. Therefore, 3D structure of hTopoIIα-DNA complex suitable for molecular modeling analysis at merbarone binding site was first generated. Using this generated complex, molecular docking analysis and molecular dynamics simulations were performed to explore the effect of merbarone on hTopoIIα-DNA complex. The binding energy for the enol form of merbarone with hTopoIIα-DNA was estimated to be -51.28 kcal/mol. The explored binding site and identified molecular recognition interactions were in accordance with the previously reported interference in the DNA-cleavage by merbarone. Virtual screening was performed using drug likeness filters, toxicity filters and ADMET descriptor based filters followed by molecular docking (ZINC database). Sixteen compounds were identified as merbarone-functional analogs suitable for hTopoIIα inhibition. These identified molecules can be considered for further evaluation of their anti-hTopoIIα activity.