Combinatorial library design and virtual screening of cryptolepine derivatives against topoisomerase IIA by molecular docking and DFT studies
-
Maria
Abstract
Various computational approaches have received ever-growing role in the design of potential inhibitors of the topoisomerase 2 (TOP2A) for cancer treatment. TOP2A plays a key role in the deoxyribonucleic acid (DNA) replication before cell division and thus facilitates the growth of cells. This TOP2A function can be suppressed by targeting it with potential inhibitors in cancer cells to terminate the uncontrolled cell division. Among potential inhibitors, cryptolepine has higher selectivity along with the ability to intercalate into DNA, effectively blocking TOP2A and ceasing cell division in cancer cells. However, this compound has drawbacks of being nonspecific and possessing relatively low affinity. Therefore, a combinatorial library of 31,114 cryptolepine derivatives was designed and virtually screened by molecular docking to predict the molecular interactions between the cryptolepine derivatives and TOP2A using cryptolepine as a standard. All the binding poses of cryptolepine derivatives for TOP2A were investigated to calculate binding energy. The compounds with the database numbers 8618, 907, 147, 16755, and 8186 scored the highest binding energies, −9.88, −9.76, −9.75, −9.73, and −9.72 kcal/mol, respectively, and the highest binding affinities while the cryptolepine binding energy is −6.09 kcal/mol. The strong binding interactions of these derivatives show that they can be used as potent TOP2A inhibitors and act as more effective anticancer agents than cryptolepine itself. The interactions of these derivatives with different amino acid residues were also observed and analyzed. A comprehensive understanding of the interactions of the proposed derivatives with TOP2A helped for searching more novel and potent drug-like molecules for anticancer therapy. This computational study suggests useful references to understand inhibition mechanisms that will help in the further modifications of TOP2A inhibitors. Moreover, the DFT study of the derivatives with the highest binding energies was performed, helping to further understand the binding affinities of these compounds.
Funding source: Institute of Chemical Sciences, University of Peshawar
Funding source: Universidad Técnica Federica Santa Maria
Funding source: Department of Chemistry, ITA
Funding source: National Laboratory for High Performance Computing
Acknowledgments
Maria and Zahid Khan deeply acknowledge the financial support of the Institute of Chemical Sciences, University of Peshawar. Aleksey E. Kuznetsov deeply acknowledges the financial support of the Universidad Técnica Federica Santa Maria (USM), Santiago, Chile, along with the computational facilities of the Department of Chemistry, ITA, Brazil, and National Laboratory for High Performance Computing (NLHPC), Chile.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This study was supported by Institute of Chemical Sciences, University of Peshawa; Universidad Técnica Federica Santa Maria (USM), Santiago, Chile along with Department of Chemistry, ITA; and National Laboratory for High Performance Computing (NLHPC), Chile.
Conflict of interest statement: The authors declare no competing financial interests.
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© 2021 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Editorial: Advanced chemoinformatics applications at the service of natural product discovery
- Combinatorial library design and virtual screening of cryptolepine derivatives against topoisomerase IIA by molecular docking and DFT studies
- Chemical similarity methods for analyzing secondary metabolite structures
- Carbonyl pigments: miscellaneous types
- Diketopyrrolopyrrole (DPP) pigments
Artikel in diesem Heft
- Frontmatter
- Editorial: Advanced chemoinformatics applications at the service of natural product discovery
- Combinatorial library design and virtual screening of cryptolepine derivatives against topoisomerase IIA by molecular docking and DFT studies
- Chemical similarity methods for analyzing secondary metabolite structures
- Carbonyl pigments: miscellaneous types
- Diketopyrrolopyrrole (DPP) pigments
