Switch in Site of Inhibition: A Strategy for Structure-Based Discovery of Human Topoisomerase IIα Catalytic Inhibitors.
A study of structure-based modulation of known ligands of hTopoIIα, an important enzyme involved in DNA processes, coupled with synthesis and in vitro assays led to the establishment of a strategy of rational switch in mode of inhibition of the enzyme's catalytic cycle. 6-Arylated derivatives of known imidazopyridine ligands were found to be selective inhibitors of hTopoIIα, while not showing TopoI inhibition and DNA binding. Interestingly, while the parent imidazopyridines acted as ATP-competitive inhibitors, arylated derivatives inhibited DNA cleavage similar to merbarone, indicating a switch in mode of inhibition from ATP-hydrolysis to the DNA-cleavage stage of catalytic cycle of the enzyme. The 6-aryl-imidazopyridines were relatively more cytotoxic than etoposide in cancer cells and less toxic to normal cells. Such unprecedented strategy will encourage research on "choice-based change" in target-specific mode of action for rapid drug discovery.
Department of Pharmaceutical Technology (Biotechnology), Department of Pharmacoinformatics, and Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
Ashish T
AT
Baviskar
Department of Pharmaceutical Technology (Biotechnology), Department of Pharmacoinformatics, and Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
Suyog M
SM
Amrutkar
Department of Pharmaceutical Technology (Biotechnology), Department of Pharmacoinformatics, and Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
Neha
N
Trivedi
Department of Pharmaceutical Technology (Biotechnology), Department of Pharmacoinformatics, and Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
Vikas
V
Chaudhary
School of Biotechnology, KIIT University , Campus-11, Patia, Bhubaneswar, Orissa 751024, India.
Anmada
A
Nayak
Department of Pharmaceutical Technology (Biotechnology), Department of Pharmacoinformatics, and Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
Sankar K
SK
Guchhait
Department of Pharmaceutical Technology (Biotechnology), Department of Pharmacoinformatics, and Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
Uttam C
UC
Banerjee
Department of Pharmaceutical Technology (Biotechnology), Department of Pharmacoinformatics, and Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, SAS Nagar, Mohali, Punjab 160062, India ; Department of Pharmaceutical Technology (Biotechnology), Department of Pharmacoinformatics, and Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
Prasad V
PV
Bharatam
School of Biotechnology, KIIT University , Campus-11, Patia, Bhubaneswar, Orissa 751024, India.
Chanakya N
CN
Kundu
Human topoisomerase IIα; anticancer agent; chemotype-modulation; drug discovery