Virtual screening and multilevel precision-based prioritisation of natural inhibitors targeting the ATPase domain of human DNA topoisomerase II alpha

Abstract

Human DNA topoisomerase II alpha (hTopIIα) is a classic chemotherapeutic drug target. The existing hTopIIα poisons cause numerous side effects such as the development of cardiotoxicity, secondary malignancies, and multidrug resistance. The use of catalytic inhibitors targeting the ATP-binding cavity of the enzyme is considered a safer alternative due to the less deleterious mechanism of action. Hence, in this study, we carried out high throughput structure-based virtual screening of the NPASS natural product database against the ATPase domain of hTopIIα and identified the five best ligand hits. This was followed by comprehensive validation through molecular dynamics simulations, binding free energy calculation and ADMET analysis. On stringent multilevel prioritization, we identified promising natural product catalytic inhibitors that showed high binding affinity and stability within the ligand-binding cavity and may serve as ideal hits for anticancer drug development.

Communicated by Ramaswamy H. Sarma

Keywords:

• Human DNA topoisomerase II alpha
• nucleotide-binding domain
• high throughput virtual screening (HTVS)
• molecular dynamics simulations
• ADMET

Disclosure statement

The authors declare that there are no conflicts of interest.

Additional information

Funding

The authors gratefully acknowledge the funding provided by the Indian Council of Medical Research, New Delhi (ICMR grant No. ISRM/12(25)/2019) for carrying out this study