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

• Published in: Bioinformation Vol. 17; no. 1; pp. 249 - 265
• Main Authors: Ayyamperumal, Selvaraj, Dj, Dhananjay, Tallapaneni, Vyshnavi, Mohan, Surender, S, Basappa, Selvaraj, Jubie, Joghee, Nanjan Moola, Mjn, Chandrasekar
• Format: Journal Article
• Language: English
• Published: Singapore Biomedical Informatics 01-01-2021
• Subjects: Anticancer properties; Antitumor activity; Antitumor agents; ATP; Binding; Cancer; Chromosomes; Coordination compounds; Crystal structure; Deoxyribonucleic acid; DNA; DNA topoisomerase (ATP-hydrolysing); Dynamic stability; Free energy; Hydrogen bonds; Inhibitors; Ligands; Molecular docking; Molecular dynamics; Molecular structure; Natural products; Protein structure; Proteins; Pyrrolidine; Selectivity; Succinimide; Topology; Toxicity; Transcription; Molecular Dynamics; Drug design; α-Topoisomerase II; Anticancer agents; ADMET; Molecular Docking
• ISSN: 0973-2063; 0973-8894; 0973-2063
• DOI: 10.6026/97320630017249

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.