The binding modes and binding affinities of epipodophyllotoxin derivatives with human topoisomerase IIα

Naik, Pradeep Kumar; Dubey, Abhishek; Soni, Komal; Kumar, Rishay; Singh, Harvinder

doi:10.1016/j.jmgm.2010.10.005

Cited by 7 publications

(7 citation statements)

References 39 publications

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“…This model positions the 4β-NH 2 -4′-DMEP in the active site, with the phenyl group interacting with the catalytic tyrosine 804 residue, and surrounding contacts with the Asp-737, Lys-738, and Gln-784 amino acids. The amino group points into an open cavity, leaving room for a diversity of substituents . In recent years, 11 new series of amino-substituted 4′-DMEP have been presented: Triazolyl derivatives, such as compound 14 (Figure ), which is more cytotoxic than etoposide in a panel of tumor cell lines. − A series of (alkyltriazolyl)epipodophyllotoxins have been reported with a satisfactory correlation between interaction with topoisomerase II (docking study in silico) and drug-induced cytotoxicity …”

Section: Epipodophyllotoxins Forevermentioning

confidence: 99%

Contemporary Challenges in the Design of Topoisomerase II Inhibitors for Cancer Chemotherapy

2012

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Section: Epipodophyllotoxins Forevermentioning

confidence: 99%

Contemporary Challenges in the Design of Topoisomerase II Inhibitors for Cancer Chemotherapy

2012

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“…Before the experimental resolution of a structure of TopoII bound to etoposide, its binding pose was defined by homology modeling and docking . In particular, etoposide and other epipodophyllotoxin derivatives were docked into a homology-constructed TopoIIα using Bimolecular Association with Energetics (eMBrAcE) program from Schrödinger .…”

Section: The State Of the Artmentioning

confidence: 99%

“…124,126,129,131 Ligand−protein interactions of several TopoII inhibitors were explored with various computational tools. 138,170,172 In particular, MM/PBSA, a method developed to estimate free energies, 231 was applied to perform per-residue energy decomposition to quantify the contribution of each residue to the ligand binding affinity. 151 This could be highly valuable to guide ligand optimization as it highlights crucial bonds and might reveal some unfavorable interactions.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…Before the experimental resolution of a structure of TopoII bound to etoposide, its binding pose was defined by homology modeling and docking. 170 In particular, etoposide and other epipodophyllotoxin derivatives were docked into a homology-constructed TopoIIα using Bimolecular Association with Energetics (eMBrAcE) program from Schrodinger. 171 Furthermore, authors built QSAR models relating intracellular concentrations of covalent TopoII-DNA complexes to the corresponding docking scores and free energies of binding.…”

Section: ■ Introductionmentioning

confidence: 99%

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The Use of Methods of Computer-Aided Drug Discovery in the Development of Topoisomerase II Inhibitors: Applications and Future Directions

Radaeva

Dong

Cherkasov

2020

J. Chem. Inf. Model.

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Topoisomerase II (TopoII) is an enzyme essential for cellular metabolism and replication as it regulates DNA topology. Since inhibition of TopoII induces cell death, it is a wellestablished drug target in cancer therapy; several broadly used anticancer drugs including etoposide and doxorubicin are TopoII inhibitors. However, these therapeutics tend to cause severe side effects and suffer from relatively low ligand affinity, leaving TopoII targeting with small molecules an active area of research. In recent years computer-aided drug discovery (CADD) approaches have been actively used to expand knowledge on the role of TopoII in cancer and to develop novel strategies for its inhibition. Herein, we overview studies that employed structurebased approaches such as docking and molecular dynamic simulations, as well as ligand-based approaches, such as QSAR (quantitative structure−activity relationship) modeling among others, to gain understanding in TopoII targeting with existing drugs and to search for novel drug candidates.

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“…Despite the wide use of Topo II targeted drugs as antitumour agents, several limitations hamper their benefits. Efforts for improving their clinical efficacy further by overcoming the drug resistance, myelosuppresion and poor bioavailability problems associated with them, were continued to be challenging 5 .…”

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confidence: 99%

Untitled

2013

IJPSR

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Topoisomerase enzymes are highly expressed in cells which undergo rapid multiplication. Inhibition of this enzyme represents a potential therapeutic approach for diseases such as cancer. In order to understand the structure activity correlation of 2, 4, 6 pyridine based topoisomerase inhibitor, we have carried out a combined pharmacophore modelling, 3D-QSAR studies, molecular docking and virtual screening studies. A five point pharmacophore with hydrogen bond acceptor (A), hydrogen bond donor (D) and three aromatic rings (R 5, R 6, R 7) was used to derive a predictive atom based 3d-qsar model. The generated model had showed good correlation coefficient for training set and test set (R 2 =0.91and Q 2 =0.827). It was also validated using enrichment factor (EF) and goodness of hit score (GH score) and was used for virtual screening of compounds from "zinc drug like database". Docking study of the hits retrieved from virtual screening revealed the binding affinity of these inhibitors at the active site of topoisomerase enzyme. In silico ADME predictions was also performed. These findings provide a set of guidelines for designing compounds with better topoisomerase inhibitory potential.

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The binding modes and binding affinities of epipodophyllotoxin derivatives with human topoisomerase IIα

Cited by 7 publications

References 39 publications

Contemporary Challenges in the Design of Topoisomerase II Inhibitors for Cancer Chemotherapy

Contemporary Challenges in the Design of Topoisomerase II Inhibitors for Cancer Chemotherapy

The Use of Methods of Computer-Aided Drug Discovery in the Development of Topoisomerase II Inhibitors: Applications and Future Directions

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