Identification and validation of novel microtubule suppressors with an imidazopyridine scaffold through structure-based virtual screening and docking

Samia A Elseginy, Sofia Oliveira, Deborah K Shoemark, Richard B Sessions*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

8 Citations (Scopus)
40 Downloads (Pure)

Abstract

Targeting the colchicine binding site of α/β tubulin microtubules can lead to suppression of microtubule dynamics, cell cycle arrest and apoptosis. Therefore, the development of microtubule (MT) inhibitors is considered a promising route to anticancer agents. Our approach to identify novel scaffolds as MT inhibitors depends on a 3D-structure-based pharmacophore approach and docking using three programs MOE, Autodock and BUDE (Bristol University Docking Engine) to screen a library of virtual compounds. From this work we identified the compound 7-(3-Hydroxy-4-methoxy-phenyl)-3-(3-trifluoromethyl-phenyl)-6,7-dihydro-3H-imidazo[4,5-b]pyridin-5-ol (6) as a novel inhibitor scaffold. This compound inhibited several types of cancer cell proliferation at low micromolar concentrations with low toxicity. Compound 6 caused cell cycle arrest in the G2/M phase and blocked tubulin polymerization at low micromolar concentration (IC50 = 6.1 ±0.1 µM), inducing apoptosis via activation of caspase 9, increasing the level of the pro-apoptotic protein Bax and decreasing the level of the anti-apoptotic protein Bcl2. In summary, our approach identified a lead compound with potential antimitotic and antiproliferative activity.
Original languageEnglish
Pages (from-to)929-943
Number of pages15
JournalRSC medicinal chemistry
Volume13
Issue number8
Early online date18 May 2022
DOIs
Publication statusE-pub ahead of print - 18 May 2022

Bibliographical note

Funding Information:
We thank the Advanced Computing Research Centre at the University of Bristol for provision of High-Performance Computing using BlueCrystal supercomputers. ASFO, DKS and RBS thank BrisSynBio (EPSRC/BBSRC: BB/L01386X/1) for support. We also acknowledge Dr. Esam Rashwan, head of confirmatory diagnostic unit, Vacsera-Egypt, for helping in performing the biological assays. We thank Dr. Amaurys Avila Ibarra for discussions and assistance with software.

Publisher Copyright:
© The Royal Society of Chemistry 2022.

Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute

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