Studies on Non-synonymous Polymorphisms Altering Human DNA Topoisomerase II-Alpha Interaction with Amsacrine and Mitoxantrone: AnIn SilicoApproach.
BACKGROUND
DNA topoisomerase II-α (Top2-α), an essential enzyme for the management of DNA during replication, transcription, recombination, and chromatin remodeling, is one of the most important anticancer targets. Numerous molecules have been designed as Top2-α inhibitors. However, several studies have shown that polymorphisms and mutations in Top2 have conferred resistance to most of these anticancer drugs. The aim of this study was to computationally examine the mechanisms by which genomic variations in Top2-α could affect its resistance to Amsacrine and Mitoxantrone as important inhibitors of the enzyme.


RESULTS
The results showed that variants K529E, R568H, R568G and T530M could affect Top2-α inhibition by Amsacrine causing possible drug-resistant. Moreover, R487K, and Y481C variants could change the response of the enzyme to Mitoxantrone.


CONCLUSIONS
These results could facilitate the prediction and development of more effective drugs for Top2-α variants, making the cancer chemotherapy more effectiv.
Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan. Iran.
Farzaneh Mohamadi
FM
Farsani
Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan. Iran.
Mohamad Reza
MR
Ganjalikhany
Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan. Iran.
Sadeq
S
Vallian
D000677:Amsacrine / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008942:Mitoxantrone / Q000737:chemistry* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D000075223:Poly-ADP-Ribose Binding Proteins / Q000737:chemistry* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D000075223:Poly-ADP-Ribose Binding Proteins; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D008942:Mitoxantrone; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human
Cancer therapy; docking; drug-resistance; non-synonymous polymorphisms; topoisomerase II; topoisomerase inhibitors