Identification of Novel Potential Tubulin-Targeting Heterocyclic Compounds via Integrated Virtual Screening and In Vitro Studies
7 affiliations
- 1Department of Pharmaceutical, Organic and Bioorganic Chemistry, , Pekarska 69, 79010 Lviv, Ukraine; (Y.D.); (N.S.); (R.L.)
- 2Chair and Department of Organic Chemistry, , Chodzki 4a, 20-093 Lublin, Poland
- 3Department of Synthesis and Technology of Drugs, , Kilinskiego 1, 15-089 Bialystok, Poland; (R.D.); (K.B.)
- 4Department of Regulation of Cell Proliferation and Apoptosis, Institute of Cell Biology of , Drahomanov14/16, 79005 Lviv, Ukraine; (N.F.); (I.I.); (Y.K.)
- 5Department of Chemistry, Pharmaceutical Analysis and Postgraduate Education, Halytska St., 124K, 76008 Ivano-Frankivsk, Ukraine;
- 6Department of Clinical Pharmacology, , Kilinskiego 1, 15-089 Bialystok, Poland;
- 7Department of Biotechnology, , Kilinskiego 1, 15-089 Bialystok, Poland; (M.P.); (A.G.); (A.B.)
Abstract
Background: The development of novel tubulin-targeting agents remains a promising strategy in anticancer drug design. In the present study, novel heterocyclic tubulin-targeting compounds were identified using a complex in silico/in vitro workflow. Methods: An in-house library of approximately 8000 structurally diverse heterocyclic compounds was screened for antiproliferative activity, yielding 260 experimentally validated hits. These compounds were docked against the colchicine, vinca, and taxane binding sites of tubulin. Selected compounds were also tested for their effects on cellular β-tubulin protein levels in Jurkat cells. Results: Docking analysis indicated that 42 compounds matched or exceeded colchicine’s binding energy, 3 compounds were comparable to vinblastine, and 18 compounds surpassed paclitaxel, suggesting the colchicine and taxane sites as preferred targets. Five top-scoring compounds (Les-6370, Les-4272, Les-4309, Les-4403, and Les-1419) were further analyzed via molecular dynamics simulations, confirming stable binding—particularly at the colchicine site—and favorable hydrogen-bonding and lipophilic interactions. At 10 µM, Les-1419 and Les-4309 reduced total cellular β-tubulin protein levels in Jurkat cells by 57.73% and 54.31%, respectively, relative to the effect observed for the reference compound Combretastatin A-4. Conclusions: This study resulted in the identification of novel starting scaffolds with favorable tubulin interaction activity and predicted drug-like properties, representing structurally novel parent structures and serving as promising starting points for further structural optimization and analogue development.
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BibTeX
@article{deyak2026identification,
title = {{Identification of Novel Potential Tubulin-Targeting Heterocyclic Compounds via Integrated Virtual Screening and In Vitro Studies}},
author = {Yaroslava Deyak and Dmytro Khylyuk and Rostyslav Dudchak and Nataliya Finiuk and Iryna Ivasechko and Yuliia Kozak and Nazar Solodiak and Halyna Derkach and Marta Pietruszyńska and Magdalena Podolak and Agnieszka Gornowicz and Krzysztof Bielawski and Anna Bielawska and Serhii Holota and Roman Lesyk},
journal = {Pharmaceuticals (Basel, Switzerland)},
year = {2026},
month = oct,
doi = {10.3390/ph19101637},
url = {https://europepmc.org/article/PMC/PMC13708617},
note = {CC BY},
}
RIS
TY - JOUR
TI - Identification of Novel Potential Tubulin-Targeting Heterocyclic Compounds via Integrated Virtual Screening and In Vitro Studies
AU - Yaroslava Deyak
AU - Dmytro Khylyuk
AU - Rostyslav Dudchak
AU - Nataliya Finiuk
AU - Iryna Ivasechko
AU - Yuliia Kozak
AU - Nazar Solodiak
AU - Halyna Derkach
AU - Marta Pietruszyńska
AU - Magdalena Podolak
AU - Agnieszka Gornowicz
AU - Krzysztof Bielawski
AU - Anna Bielawska
AU - Serhii Holota
AU - Roman Lesyk
PY - 2026
DA - 2026/10/01
JO - Pharmaceuticals (Basel, Switzerland)
DO - 10.3390/ph19101637
UR - https://europepmc.org/article/PMC/PMC13708617
AB - Background: The development of novel tubulin-targeting agents remains a promising strategy in anticancer drug design. In the present study, novel heterocyclic tubulin-targeting compounds were identified using a complex in silico/in vitro workflow. Methods: An in-house library of approximately 8000 structurally diverse heterocyclic compounds was screened for antiproliferative activity, yielding 260 experimentally validated hits. These compounds were docked against the colchicine, vinca, and taxane binding sites of tubulin. Selected compounds were also tested for their effects on cellular β-tubulin protein levels in Jurkat cells. Results: Docking analysis indicated that 42 compounds matched or exceeded colchicine’s binding energy, 3 compounds were comparable to vinblastine, and 18 compounds surpassed paclitaxel, suggesting the colchicine and taxane sites as preferred targets. Five top-scoring compounds (Les-6370, Les-4272, Les-4309, Les-4403, and Les-1419) were further analyzed via molecular dynamics simulations, confirming stable binding—particularly at the colchicine site—and favorable hydrogen-bonding and lipophilic interactions. At 10 µM, Les-1419 and Les-4309 reduced total cellular β-tubulin protein levels in Jurkat cells by 57.73% and 54.31%, respectively, relative to the effect observed for the reference compound Combretastatin A-4. Conclusions: This study resulted in the identification of novel starting scaffolds with favorable tubulin interaction activity and predicted drug-like properties, representing structurally novel parent structures and serving as promising starting points for further structural optimization and analogue development.
SN - 1424-8247
ER -