Structural Changes, Biological Consequences, and Repurposing of Colchicine Site Ligands

Montecinos, Felipe; Sackett, Dan L.

doi:10.3390/biom13050834

Cited by 3 publications

(1 citation statement)

References 47 publications

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“…The compound can be added to the long list of colchicine-site tubulin-binding alkaloids. This site is known to be is promiscuous, capable of accommodating a broad range of structurally distinct molecules that can vary in size, shape, and affinity [46]. Nevertheless, it is an attractive site for drug binding and drug design [47,48].…”

Section: Discussionmentioning

confidence: 99%

Interaction of Norsecurinine-Type Oligomeric Alkaloids with α-Tubulin: A Molecular Docking Study

Vergoten,

Bailly

2024

Plants

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The medicinal plant Securinega virosa (Roxb ex. Willd) Baill., also known as Flueggea virosa (Roxb. ex Willd.) Royle, is commonly used in traditional medicine in Africa and Asia for the management of diverse pathologies, such as parasite infections, diabetes, and gastrointestinal diseases. Numerous alkaloids have been isolated from the twigs and leaves of the plant, notably a variety of oligomeric indolizidine alkaloids derived from the monomers securinine and norsecurinine which both display anticancer properties. The recent discovery that securinine can bind to tubulin and inhibit microtubule assembly prompted us to investigate the potential binding of two series of alkaloids, fluevirosines A–H and fluevirosinine A-J, with the tubulin dimer by means of molecular modeling. These natural products are rare high-order alkaloids with tri-, tetra-, and pentameric norsecurinine motifs. Despite their large size (up to 2500 Å3), these alkaloids can bind easily to the large drug-binding cavity (about 4800 Å3) on α-tubulin facing the β-tubulin unit. The molecular docking analysis suggests that these hydrophobic macro-alkaloids can form stable complexes with α/β-tubulin. The tubulin-binding capacity varies depending on the alkaloid size and structure. Structure-binding relationships are discussed. The docking analysis identifies the trimer fluevirosine D, tetramer fluevirosinine D, and pentamer fluevirosinine H as the most interesting tubulin ligands in the series. This study is the first to propose a molecular target for these atypical oligomeric Securinega alkaloids.

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Section: Discussionmentioning

confidence: 99%

Interaction of Norsecurinine-Type Oligomeric Alkaloids with α-Tubulin: A Molecular Docking Study

Vergoten,

Bailly

2024

Plants

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The novel herbicide icafolin‐methyl is a plant‐specific inhibitor of tubulin polymerization

Haaf,

Peters,

Laber

et al. 2024

Pest Management Science

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BACKGROUNDWithout controlling weeds, it is estimated that about one third of global crop yields would be lost. Herbicides remain the most effective solution for weed control, but they face multiple challenges, such as the emergence and growth of resistant weed populations. Consequently, there is an urgent need for either herbicides with new modes of action or at least novel chemistries within established modes of action, with outstanding efficacy but without showing cross‐resistance to the herbicides present in the prospective markets.RESULTSIcafolin‐methyl is a novel herbicide with a unique biological profile. It is hydrolyzed in planta to the carboxylic acid icafolin. After post‐emergence application icafolin‐methyl and icafolin both show high efficacy against the most relevant competitive weeds in cold and warm season cropping systems at low application rates, including resistant black‐grass and rye‐grass biotypes. Biochemical and genetic evidence is provided that icafolin‐methyl and icafolin inhibit plant tubulin polymerization probably by binding to ß‐tubulins.CONCLUSIONIcafolin‐methyl is a novel non‐selective herbicide with an established mode of action, but with a superior potency and spectrum, specifically after foliar application. This makes icafolin‐methyl fundamentally different from existing tubulin polymerization inhibiting herbicides. It complements the farmers weed control toolbox, particularly with respect to resistance management. © 2024 Society of Chemical Industry.

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Interaction of norsecurinine-type monomeric and dimeric alkaloids with α-tubulin: a molecular docking study

Vergoten,

Bailly

2024

Explor Drug Sci

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Aim: New microtubule-targeting agents are needed to improve cancer treatment. The recent characterization of the anticancer alkaloid securinine as a tubulin-binding agent prompted us to explore the interaction of related monomeric and dimeric analogues with tubulin. The interaction between the α/β-tubulin dimer and alkaloids fluevirines A–F and flueggenines A–I, isolated from the bush Flueggea virosa (Roxb. ex Willd.) Royle, was investigated using molecular docking. Methods: Two molecular models were initially compared for the binding of securinine to α/β-tubulin. The pironetin-binding site model (5FNV) was selected for the subsequent docking analysis with all compounds. Empirical energies of interaction (ΔE) were measured and compared. Results: Fluevirine A has been identified as a potent tubulin binder. This dimeric alkaloid formed more stable complexes with tubulin than the monomeric counterparts, such as fluevirines B–D. The bis-indole derivative fluevirine E also provided more stable complexes than (nor)securinine. The study was extended to the dimeric alkaloids flueggenines A–I and three compounds were identified as potential tubulin binders: the polycyclic product flueggenine B, the norsecurinine-indole hybrid flueggenine E, and the norsecurinine dimer flueggenine I. This later compound proved to be well adapted to fit into the pironetin site of tubulin, extending its two norsecurinine units between the colchicine-binding area and the pironetin site, in close proximity to the pironetin-reactive cysteine-316 residue. Structure-binding relationships were delineated. Conclusions: The study identifies the dimeric alkaloids fluevirine A and flueggenine I as potential α-tubulin binding agents. For the first time, dimeric alkaloids including two C-C connected norsecurinine units are characterized as tubulin ligands. The study contributes to a better understanding of the mechanism of action of Flueggea alkaloids and should help the design of anticancer analogues targeting the pironetin site of α-tubulin.

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Structural Changes, Biological Consequences, and Repurposing of Colchicine Site Ligands

Cited by 3 publications

References 47 publications

Interaction of Norsecurinine-Type Oligomeric Alkaloids with α-Tubulin: A Molecular Docking Study

Interaction of Norsecurinine-Type Oligomeric Alkaloids with α-Tubulin: A Molecular Docking Study

The novel herbicide icafolin‐methyl is a plant‐specific inhibitor of tubulin polymerization

Interaction of norsecurinine-type monomeric and dimeric alkaloids with α-tubulin: a molecular docking study

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