New Imidazole Inhibitors of Mycobacterial FtsZ: the Way from High-Throughput Molecular Screening in Grid up to in vitro Verification

Карпов, П. А.; Demchuk, Oleg M.; Britsun, V.M.; Lytvyn, Dmytro I.; Pydiura, Nikolay; Rayevsky, Alexey; Samofalova, Dariia; Spivak, S. I.; Volochnyuk, Dmitriy M.; Yemets, А. І.; Blume, Ya. B.

doi:10.15407/scine12.03.043

Cited by 7 publications

(2 citation statements)

References 17 publications

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“…Завданням цього дослідження було визначення ключових білкових мішеней представників Mycobacterium та встановлення структурних особливостей їх взаємодії з відомими сполуками для подальшої розробки нових лікарських препаратів проти туберкульозу. За основу дослідження було взято протокол, розроблений у ВО CSLabGrid [14,15], проте до нього було додано нові модулі: супровід in vitro і / або in situ верифікації результатів та ІТпідтримку. Як референсні структури білків були використані експериментальні структури мішеней із різних штамів Mycobacterium (більш ніж 50 якісних структур, за даними RCSB Protein Data Bank, x-Ray<2,0 Å), що дозволило виконати аналіз рівня подібності сайтів зв'язування лігандів, водночас у якості референсних структур для потенційних інгібіторів були використані хімічні речовини проти цільових сполук (зокрема, більш ніж 4400 унікальних ефекторів проти M. tuberculosis, за даними BindingDB).…”

Section: аналіз механізмів взаємодії основних мішеней таргетної терапії туберкульозу з їх селективними інгібіторамиunclassified

Analysis of interaction mechanisms between main objects of tuberculosis-target therapy and corresponding selective inhibitors

Samofalova¹,

Rayevsky²,

Ozheredov³

et al. 2021

Fakt. eksp. evol. org.

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Aim. Search for new inhibitors of the mitotic apparatus of mycobacterium and a number of enzymatic targets. Methods. 3D models of key targets reconstruction and geometry optimization and analysis of biologically active conformations of inhibitors were performed according to a previously developed technique. Results. A revision of mycobacterial inhibitors, which exhibit antimicrobial action against representatives of the genus Mycobacterium, was carried out, which made it possible to create an appropriate reference library of compounds. The complete spatial structure of a number of the main targets of targeted therapy for tuberculosis was reconstructed and verified, and the features of their interaction with selective inhibitors were established. Chemogenomic profiling was performed, which made it possible to draw conclusions regarding the uniqueness of the studied sites and the potential toxicity of compounds related to these sites for humans. Conclusions. A well-developed search algorithm for known inhibitors of proteins with M. tuberculosis allows further study of the features of their interaction with the corresponding homologues of M. bovis and the development of new, more selective compounds using molecular dynamics and docking methods. Keywords: tuberculosis, in silico, anti-tuberculosis drugs.

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Analysis of interaction mechanisms between main objects of tuberculosis-target therapy and corresponding selective inhibitors

Samofalova¹,

Rayevsky²,

Ozheredov³

et al. 2021

Fakt. eksp. evol. org.

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“…Попередні дослідження x-Ray структур довели, що зв'язування гетероциклічних сполук на поверхні молекул тубулінів може здійснюватися за чотирма пріоритетними сайтами: 1) GTP/GSP; 2) TZT; 3) HOS/T131 і 4) Taxol [14]. Для високопропускного молекулярного скринінгу сполук із фунгіцидною дією нами було використано ГТФ/ГДФ-обмінний сайт і сайт зв'язування таксолу.…”

Section: результати та обговоренняunclassified

A high-throughput virtual screening in Grid for new tubulin-targeted inhibitors of plant fungal pathogens

Карпов¹,

Demchuk²,

Rayevsky³

et al. 2018

Fakt. eksp. evol. org.

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Aim. To select new tubulin-targeted inhibitors of plant fungal pathogens based on results of high-throughput virtual screening in Grid. Methods. Protein and ligand spatial structure modelling (I-Tasser, Grid), design and virtual screening ligands library (UCSF Dock 6, Grid), molecular docking (CCDC Gold), molecular dynamics simulation (Gromacs, Grid). Results. 240 structural models of tubulin molecules (82 α-, 111 β- and 47 γ-tubulin) from 62 species of phytopathogenic fungi were constructed. It was found that imidazole ligands, demonstrate strongest affinity to α- and β-tubulin. It was found that among α-, β- and γ-tubulin, taxol binding site of β-tubulin possess the strongest potential as the fungicidal drugs target. It was selected 50 leader compounds: 23 with affinity for GTP/GDF-exchange site and 27 with affinity for taxol-binding site. Conclusions. It was found, that in phytopathogenic fungi, taxol binding site of β-tubulin are the main fungicid drug target (in compare to other tubulin site or isotype). The highest affinity was predicted for the compounds F0478-0219, F0478-0166 and β-tubulin from Puccinia graminis f. sp. Tritici, as well as for the compound F0478-0385 and β-tubulin from Magnaporthe oryzae. Keywords: pathogenic fungi, fungicides, tubulin, virtual screening, Grid.

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Structure‐based virtual screening and biological evaluation of novel inhibitors of mycobacterium Z‐ring formation

Rayevsky

Dariya

Liudmyla

et al. 2022

J of Cellular Biochemistry

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The major part of commercial prodrugs against Mycobacterium tuberculosis (Mtb) demonstrated a significant inhibitory effect on cell division and inhibition of bacterial growth in vitro. However, further implementation often failed to overcome the compensatory system of interchangeable cascades. This is the most common situation for the compounds, which hit the key enzymes activities involved in all basic stages of the cell cycle. We decided to find more compounds, which could affect a cytoskeleton complex playing important role in sensing the external signals, intracellular transport, and cell division. In general, the bacterial cytoskeleton is crucial for response to the environment and participates in cell-to-cell communication. In turn, filamentous temperature-sensitive Z (FtsZ) protein, a mycobacterial tubulin homolog, is essential for Z-ring formation and further bacteria cell division. We predicted the most preferable binding-sites and conducted a highthroughput virtual screening. Modeling results suggest that some compounds bind in a specific region on the surface Mtb FtsZ, which is absent in human, and other could hit GTPase activity of the FtsZ. Further in vitro studies confirmed that these novel molecules can efficiently bind to these pockets, demonstrating an effect on the polymerization state and kinetics mechanisms.The rescaling of the experiment on the cell line revealed that reported

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New Imidazole Inhibitors of Mycobacterial FtsZ: the Way from High-Throughput Molecular Screening in Grid up to in vitro Verification

Cited by 7 publications

References 17 publications

Analysis of interaction mechanisms between main objects of tuberculosis-target therapy and corresponding selective inhibitors

Analysis of interaction mechanisms between main objects of tuberculosis-target therapy and corresponding selective inhibitors

A high-throughput virtual screening in Grid for new tubulin-targeted inhibitors of plant fungal pathogens

Structure‐based virtual screening and biological evaluation of novel inhibitors of mycobacterium Z‐ring formation

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