Molecular Docking of Cryptoconcatones to α-Tubulin and Related Pironetin Analogues

Vergoten, Gérard; Bailly, Christian

doi:10.3390/plants12020296

Cited by 8 publications

(9 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This moiety can be found in plagiochilin Q and recently, we showed that a related series of natural products with a 5,6-dihydro-α-pyrone unit, the cryptoconcatones, can function as α-tubulin-binding agents. Notably, we identified cryptoconcatones F and L as robust α-tubulin binders capable of forming covalent protein adducts [38]. We also evidenced the cytotoxic lactone spicigerolide with a pyranone moiety as a tubulin binder.…”

Section: Discussionmentioning

confidence: 74%

The Plagiochilins From Liverworts Plagiochila: Binding to α-Tubulin and Drug Design Perspectives

Bailly¹,

VERGOTEN²

2023

Preprint

View full text Add to dashboard Cite

Among bryophytes, the Plagiochila genus represents a large group of leafy liverworts, with over 500 species. Plagiochilins A-to-X are sesquiterpenoids isolated from Plagiochila species. The lead compound plagiochilin A (Plg-A), endowed with anticancer and anti-parasitic properties, has been characterized as a potent mitosis inhibitor, acting selectively at the late stage of cytokinesis termed abscission. The compound perturbs the dynamic of microtubules, blocking cell cycle progression and triggering the death of malignant cells. Based on the compound mechanism of action and the analogy with other natural products bearing a dihydro-pyrone moiety, we postulated that Plg-A could bind to the pironetin site of α-tubulin. A molecular docking analysis has been performed to compare binding of all 24 plagiochilins to α-tubulin and to establish structure-binding relationships. The identification of Plg-E and Plg-G as the best binders in the series pointed out to the importance of the C13-OH or C=O group for α-tubulin recognition. This observation led to the testing of the natural product ester plagiochilin A-15-yl n-octanoate and the corresponding alcohol (Plg-OH), both identified as robust α-tubulin binders. The study provides a rational to explain potentially the mechanism of action of Plg-A and to guide the design of new derivatives.

show abstract

Section: Discussionmentioning

confidence: 74%

The Plagiochilins From Liverworts Plagiochila: Binding to α-Tubulin and Drug Design Perspectives

Bailly¹,

VERGOTEN²

2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Same models in panels (d-f) for compound (5). The modeling analysis was performed as previously described in [109,110]. The docking process has been described previously [109,110].…”

Section: Potential Molecular Targets Of Prieurianin and Analogsmentioning

confidence: 99%

“…The modeling analysis was performed as previously described in [109,110]. The docking process has been described previously [109,110]. The docking analysis was performed with Hsp47 (PDB code 3ZHA [111]), keeping the following amino acids totally flexible: Arg222, Tyr245, Asp247, Met271, His273, Leu381, Tyr383, Asp385, His386 and Arg11 (E collagen unit).…”

Section: Potential Molecular Targets Of Prieurianin and Analogsmentioning

confidence: 99%

See 1 more Smart Citation

Insights into the Mechanism of Action of the Degraded Limonoid Prieurianin

Vergoten,

Bailly

2024

IJMS

Self Cite

View full text Add to dashboard Cite

Limonoids are extremely diversified in plants, with many categories of products bearing an intact, rearranged or fragmented oxygenated scaffold. A specific subgroup of fragmented or degraded limonoids derives from the tetranortriterpenoid prieurianin, initially isolated from the tree Trichilia prieuriana but also found in other plants of the Meliaceae family, including the more abundant species Aphanamixis polystachya. Prieurianin-type limonoids include about seventy compounds, among which are dregeanin and rohitukin. Prieurianin and analogs exhibit insecticidal, antimicrobial, antiadipogenic and/or antiparasitic properties but their mechanism of action remains ill-defined at present. Previous studies have shown that prieurianin, initially known as endosidin 1, stabilizes the actin cytoskeleton in plant and mammalian cells via the modulation of the architecture and dynamic of the actin network, most likely via interference with actin-binding proteins. A new mechanistic hypothesis is advanced here based on the recent discovery of the targeting of the chaperone protein Hsp47 by the fragmented limonoid fraxinellone. Molecular modeling suggested that prieurianin and, to a lesser extent dregeanin, can form very stable complexes with Hsp47 at the protein–collagen interface. Hsp-binding may account for the insecticidal action of the product. The present review draws up a new mechanistic portrait of prieurianin and provides an overview of the pharmacological properties of this atypical limonoid and its chemical family.

show abstract

“…In this context, one of the potential mechanisms could be a direct binding of the compound to α-tubulin, in particular to the pironetin-binding site which is known to accommodate compounds bearing a dihydro-pyrone moiety [ 65 , 66 ]. This moiety can be found in plagiochilin Q, for example, and recently, we have shown that natural products with a 5,6-dihydro-α-pyrone unit (cryptoconcatones) can function as α-tubulin-binding agents [ 67 ]. Based on these considerations, we have initiated binding studies of plagiochilins to α-tubulin and the first information obtained by molecular docking look interesting.…”

Section: Pharmacological Properties and Mechanism Of Action Of The Pl...mentioning

confidence: 99%

Discovery and Anticancer Activity of the Plagiochilins from the Liverwort Genus Plagiochila

Bailly

2023

Life

Self Cite

View full text Add to dashboard Cite

The present analysis retraces the discovery of plagiochilins A-to-W, a series of seco-aromadendrane-type sesquiterpenes isolated from diverse leafy liverworts of the genus Plagiochila. Between 1978, with the first isolation of the leader product plagiochilin A from P. yokogurensis, and 2005, with the characterization of plagiochilin X from P. asplenioides, a set of 24 plagiochilins and several derivatives (plagiochilide, plagiochilal A-B) has been isolated and characterized. Analogue compounds recently described are also evoked, such as the plagiochianins and plagicosins. All these compounds have been little studied from a pharmacological viewpoint. However, plagiochilins A and C have revealed marked antiproliferative activities against cultured cancer cells. Plagiochilin A functions as an inhibitor of the termination phase of cytokinesis: the membrane abscission stage. This unique, innovative mechanism of action, coupled with its marked anticancer action, notably against prostate cancer cells, make plagiochilin A an interesting lead molecule for the development of novel anticancer agents. There are known options to increase its potency, as deduced from structure–activity relationships. The analysis shed light on this family of bryophyte species and the little-known group of bioactive terpenoid plagiochilins. Plagiochilin A and derivatives shall be further exploited for the design of novel anticancer targeting the cytokinesis pathway.

show abstract

Molecular Docking of Cryptoconcatones to α-Tubulin and Related Pironetin Analogues

Cited by 8 publications

References 59 publications

The Plagiochilins From Liverworts Plagiochila: Binding to α-Tubulin and Drug Design Perspectives

The Plagiochilins From Liverworts Plagiochila: Binding to α-Tubulin and Drug Design Perspectives

Insights into the Mechanism of Action of the Degraded Limonoid Prieurianin

Discovery and Anticancer Activity of the Plagiochilins from the Liverwort Genus Plagiochila

Contact Info

Product

Resources

About