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Molecular docking analysis of α-Topoisomerase II with δ-Carboline derivatives as potential anticancer agents


Selvaraj Ayyamperumal1, Dhananjay DJ3, Vyshnavi Tallapaneni1, Surender Mohan3, Basappa S4, Jubie Selvaraj1, Nanjan Moola Joghee2, Chandrasekar MJN*,1



1Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris-643001,Tamil Nadu, India; 2PG Studies and Research, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris- 643001, Tamil Nadu, India; 3Laboratory of Molecular Biology and Genetic Engineering, School of Biotechnology, Jawaharlal Nehru University, New Delhi-110067, India; 4Department of Studies in Organic Chemistry, University of Mysore,Manasagangotri, Mysore-570006, Karnataka, India;



Prof. M.J.N Chandrasekar - E-mail: ncsekar@jssuni.edu.in


Article Type

Research Article



Received December 30, 2020; Revised January 30, 2020; Accepted January 31, 2020, Published January 31, 2021



The enzyme, α-topoisomerase II (α-Topo II), is known to regulate efficiently the topology of DNA. It is highly expressed in rapidly proliferating cells and plays an important role in replication, transcription and chromosome organisation. This has prompted several investigators to pursue α-Topo II inhibitors as anticancer agents. δ-Carboline, a natural product, and its synthetic derivatives are known to exert potent anticancer activity by selectively targeting α-Topo II. Therefore, it is of interest to design carboline derivatives fused with pyrrolidine-2,5-dione in this context. δ-Carbolines fused with pyrrolidine-2,5-dione are of interest because the succinimide part of fused heteroaromatic molecule can interact with the ATP binding pocket via the hydrogen bond network with selectivity towards α-Topo II. The 300 derivatives designed were subjected to the Lipinski rule of 5, ADMET and toxicity prediction. The designed compounds were further analysed using molecular docking analysis on the active sites of the α-Topo II crystal structure (PDB ID:1ZXM). Molecular dynamic simulations were also performed to compare the binding mode and stability of the protein-ligand complexes. Compounds with ID numbers AS89, AS104, AS119, AS209, AS239, AS269, and AS299 show good binding activity compared to the co-crystal ligand. Molecular Dynamics simulation studies show that the ligand binding to α-Topo II in the ATP domain is stableand the protein-ligand conformation remains unchanged. Binding free energy calculations suggest that seven molecules designed are potential inhibitors for α-Topo II for further consideration as anticancer agents.



Drug design; ADMET; Molecular Docking; Molecular Dynamics; α-Topoisomerase II; Anticancer agents.



Ayyamperumal et al. Bioinformation 17(1): 249-265 (2021)


Edited by

P Kangueane






Biomedical Informatics



This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.