Molecular docking and molecular dynamics simulation identify a novel Radicicol derivative that predicts exclusive binding to<i>Plasmodium falciparum</i>Topoisomerase VIB

Bansod, Shephali; Raj, Navya; Revikumar, Amjesh; Nair, Achuthsankar S.; Bhattacharyya, Sunanda

doi:10.1080/07391102.2021.1891970

Cited by 9 publications

(7 citation statements)

References 41 publications

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“…In the Plasmodium topoisomerase, VIB, the ATP-binding domain, which spans from amino acids 22 to 166, is homologous to the one in the GHKL ATPase protein family that constitutes the Bergerat fold [ 72 ]. There is a unique stretch of highly charged amino acids spanning 61−78 within the ATPase domain [ 73 ] whose function has not yet been identified. PfTopo VIA harbors the CAP and TOPRIM domains that share 34.8% and 57% sequence similarity with SsTopo VIA, respectively.…”

Section: Type II Dna Topoisomerasementioning

confidence: 99%

“…It was found that Radicicol competes with ATP for binding to the ATPase pocket (Bergerat fold) of Topo VIB, effectively blocking nucleotide-mediated dimerization of the Topo VIB subunits [ 83 ]. Using the SsTopo VIB structure as a template, an in silico model of PfTopo VIB was built and Radicicol was found to dock in the ATP binding pocket of PfTopo VIB, similar to SsTopo VIB [ 73 ]. When tested in a P. falciparum 3D7 culture, Radicicol inhibited parasite growth with an IC 50 of 8 μM [ 84 ].…”

Section: Inhibitors Against Plasmodium Topoisomerasesmentioning

confidence: 99%

“…In a recent study, the binding affinities of 98 Radicicol derivatives with the in silico models of PfTopo VIB and PfHsp90 were predicted. Some derivatives were predicted to bind strongly with PfTopo VIB but not with PfHsp90 [ 73 ]. These approaches can be used to design specific PfTopo VIB inhibitors which improve the understanding of the PfTopo VIB's role in malaria parasite biology.…”

Section: Unanswered Questionsmentioning

confidence: 99%

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A tale of topoisomerases and the knotty genetic material in the backdrop of Plasmodium biology

et al. 2022

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The untangling or overwinding of genetic material is an inevitable part of DNA replication, repair, recombination, and transcription. Topoisomerases belong to a conserved enzyme family that amends DNA topology during various processes of DNA metabolism. To relax the genetic material, topoisomerases transiently break the phosphodiester bond on one or both DNA strands and remain associated with the cleavage site by forming a covalent enzyme–DNA intermediate. This releases torsional stress and allows the broken DNA to be re-ligated by the enzyme. The biological function of topoisomerases ranges from the separation of sister chromatids following DNA replication to the aiding of chromosome condensation and segregation during mitosis. Topoisomerases are also actively involved in meiotic recombination. The unicellular apicomplexan parasite, Plasmodium falciparum, harbors different topoisomerase subtypes, some of which have substantially different sequences and functions from their human counterparts. This review highlights the biological function of each identified Plasmodium topoisomerase along with a comparative analysis of their orthologs in human or other model organisms. There is also a focus on recent advancements towards the development of topoisomerase chemical inhibitors, underscoring the druggability of unique topoisomerase subunits that are absent in humans. Plasmodium harbors three distinct genomes in the nucleus, apicoplast, and mitochondria, respectively, and undergoes non-canonical cell division during the schizont stage of development. This review emphasizes the specific developmental stages of Plasmodium on which future topoisomerase research should focus.

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Section: Type II Dna Topoisomerasementioning

confidence: 99%

Section: Inhibitors Against Plasmodium Topoisomerasesmentioning

confidence: 99%

Section: Unanswered Questionsmentioning

confidence: 99%

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A tale of topoisomerases and the knotty genetic material in the backdrop of Plasmodium biology

et al. 2022

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“…This was thought to be through radicicol activity in abrogating parasite mitochondrial replication [ 158 ]. In addition, findings from direct binding assays suggested that radicicol elicited its antiparasitic activity through binding to either of two potential target genes, topoisomerase VIA /VIB [ 158 , 159 ] or to the mitochondrial PfHsp90_M (Trap1; [ 160 ]). The side-by-side comparative binding analysis between these genes has not been confirmed.…”

Section: P Falciparum Hsp90 As Drug Targetsmentioning

confidence: 99%

“…However, this suggests that the potential radicicol cross-reactivity with both PfHsp90_M and topoisomerases is based on the shared Bergerat ATP binding pocket. With this promising evidence, there has been revived interest in radicicol scaffold modifications towards targeting topoisomerases [ 160 ]. It remains to be validated if these radicicol derivatives targeting isomerases do indeed cross-react with parasite Hsp90s.…”

Section: P Falciparum Hsp90 As Drug Targetsmentioning

confidence: 99%

Inhibitors of the Plasmodium falciparum Hsp90 towards Selective Antimalarial Drug Design: The Past, Present and Future

Stofberg

Caillet

Villiers

et al. 2021

Cells

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Malaria is still one of the major killer parasitic diseases in tropical settings, posing a public health threat. The development of antimalarial drug resistance is reversing the gains made in attempts to control the disease. The parasite leads a complex life cycle that has adapted to outwit almost all known antimalarial drugs to date, including the first line of treatment, artesunate. There is a high unmet need to develop new strategies and identify novel therapeutics to reverse antimalarial drug resistance development. Among the strategies, here we focus and discuss the merits of the development of antimalarials targeting the Heat shock protein 90 (Hsp90) due to the central role it plays in protein quality control.

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Exploring biogenic chalcones as DprE1 inhibitors for antitubercular activity via in silico approach

et al. 2023

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Molecular docking and molecular dynamics simulation identify a novel Radicicol derivative that predicts exclusive binding toPlasmodium falciparumTopoisomerase VIB

Cited by 9 publications

References 41 publications

A tale of topoisomerases and the knotty genetic material in the backdrop of Plasmodium biology

A tale of topoisomerases and the knotty genetic material in the backdrop of Plasmodium biology

Inhibitors of the Plasmodium falciparum Hsp90 towards Selective Antimalarial Drug Design: The Past, Present and Future

Exploring biogenic chalcones as DprE1 inhibitors for antitubercular activity via in silico approach

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